Harnessing the therapeutic potential of anticancer drugs through amorphous solid dispersions

Journal Pre-proof Harnessing the therapeutic potential of anticancer drugs through amorphous solid dispersions

Urvi H. Gala, Dave A. Miller, Robert O. Williams PII:

S0304-419X(19)30160-X

DOI:

https://doi.org/10.1016/j.bbcan.2019.188319

Reference:

BBACAN 188319

To appear in:

BBA - Reviews on Cancer

Received date:

17 September 2019

Revised date:

28 October 2019

Accepted date:

28 October 2019

Please cite this article as: U.H. Gala, D.A. Miller and R.O. Williams, Harnessing the therapeutic potential of anticancer drugs through amorphous solid dispersions, BBA Reviews on Cancer(2018), https://doi.org/10.1016/j.bbcan.2019.188319

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© 2018 Published by Elsevier.

Journal Pre-proof Harnessing the Therapeutic Potential of Anticancer Drugs through Amorphous Solid Dispersions Urvi H. Gala, MS1 [email protected], Dave A. Miller, Ph.D.2 [email protected], Robert O. (Bill) Williams III, Ph.D.3 [email protected] 1

PhD Candidate, Molecular Pharmaceutics and Drug Delivery Division, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, Austin, Texas 78712 2

Vice President – R&D, DisperSol Technologies, LLC, 111 W. Cooperative Way, Building 3, Suite 300, Georgetown, TX 78626 3

Johnson & Johnson Centennial Chair and Professor, Division Head, Molecular Pharmaceutics and Drug Delivery 4

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Corresponding author.

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Editor-in-Chief, AAPS PharmSciTech, FAAPS, FAIMBE, The University of Texas at Austin, College of Pharmacy, 2409 West University Avenue, PHR 4.214, Austin, TX 78712

Journal Pre-proof Abstract

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The treatment of cancer is still a major challenge. But tremendous progress in anticancer drug discovery and development has occurred in the last few decades. However, this progress has resulted in few effective oncology products due to challenges associated with anticancer drug delivery. Oral administration is the most preferred route for anticancer drug delivery, but the majority of anticancer drugs currently in product pipelines and the majority of those that have been commercially approved have inherently poor water solubility, and this cannot be mitigated without compromising their potency and stability. The poor water solubility of anticancer drugs, in conjunction with other factors, leads to suboptimal pharmacokinetic performance. Thus, these drugs have limited efficacy and safety when administered orally. The amorphous solid dispersion (ASD) is a promising formulation technology that primarily enhances the aqueous solubility of poorly water-soluble drugs. In this review, we discuss the challenges associated with the oral administration of anticancer drugs and the use of ASD technology in alleviating these challenges. We emphasize the ability of ASDs to improve not only the pharmacokinetics of poorly water-soluble anticancer drugs, but also their efficacy and safety. The goal of this paper is to rationalize the application of ASD technology in the formulation of anticancer drugs, thereby creating superior oncology products that lead to improved therapeutic outcomes.

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Keywords: Amorphous Solid Dispersions, Anticancer Drugs, Poor Water Solubility, Oral Delivery, Pharmacokinetics, Efficacy.

Journal Pre-proof 1. Introduction: Cancer is a major global health problem. It is one of the leading causes of death worldwide [1]. According to the American Cancer Society’s 2019 statistics, about 1,762,450 new cancer cases and 606,880 cancer-related deaths are projected to occur in the United States alone [2]. Thus, the ever-increasing burden of cancer treatment not only necessitates the discovery and development of new anticancer drugs, but it also calls for the improvement of existing anticancer drugs.

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Despite the enormity of the research in the anticancer drug discovery and development space, the success rate for anticancer drugs has remained consistently poor for years [3]. It has been estimated that, only 1 of every 5,000–10,000 prospective anticancer agents receives FDA approval, and only 5% of anticancer drugs entering Phase I clinical trials are ultimately approved [4]. In a recent study, the overall probability of new anticancer drugs successful passing from Phase I to approval was found to be unacceptably low, at 3.7% [5]. One of the causes of such a high attrition rate for new anticancer drugs is their poor pharmacokinetics, which largely stems from their poor water solubility [6-9]. It has been estimated that about 75% of new drug development candidates have poor water solubility, and many of these are anticancer drugs [7].

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Another approach being explored for anticancer drug development is repurposing, which involves exploring approved non-anticancer drugs for anticancer activity. This approach also faces challenges due to a lack of optimal physicochemical properties of these drugs, such as poor water solubility, which limits their application in oncology [10]. For instance, Rapamycin, an immunosuppressant, has shown promising anticancer activity, but has poor water solubility and thus attempts are being made to derive its more soluble analogs, in order to facilitate its use in oncology [11, 12]. Among the existing approved oral anticancer drugs, about 65% have poor water solubility and thus they do not achieve their potential therapeutic outcomes with maximum efficacy and minimum toxicity [13].

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Oral administration is the most preferred route of drug delivery for anticancer drugs [14]. It offers several advantages, such as ease of administration and reduced therapy cost. Oral administration allows for feasible continuous drug administration [14-16]. One of the prerequisites for successful oral chemotherapy is achieving a reliable and consistent pharmacokinetic profile for the drugs, which enables maximum drug efficacy and minimal toxicity. However, several challenges are associated with the physicochemical properties of drugs and the physiology of the gastrointestinal tract. These challenges limit the achievement of desirable pharmacokinetics, thus they also limit the pharmacodynamics of orally administered, poorly water-soluble anticancer drugs. The poor water solubility of anticancer drugs leads to suboptimum formulations or requires the use of excipients that have toxic side effects. For example, Nexavar® (sorafenib tosylate), an orally administered kinase inhibitor is used in the treatment of hepatocellular and renal cell carcinoma [17, 18]. According to the biopharmaceutical classification system (BCS), sorafenib belongs to BCS Class II, which is characterized by low solubility and high permeability. Thus, sorafenib has unacceptably low and slow dissolution in the gastrointestinal tract, which is a rate-limiting step in

Journal Pre-proof its absorption and, along with its first-pass metabolism, results in low oral bioavailability and wide intersubject variability [19]. Thus, the poor water solubility of sorafenib leads to either subtherapeutic outcomes or acute toxicity [20, 21]. Paclitaxel, a well-known anticancer drug, has poor water solubility (< 0.03 mg·mL−1) [22]. Thus, the intravenous formulation Taxol® was developed using Cremophor EL (polyethoxylated castor oil) and ethanol to solubilize paclitaxel [23]. The use of Cremophor EL led to acute hypersensitivity reactions in patients. Despite the use of premedication, reactions still occurred in ~44% of patients, and potentially life-threatening reactions occurred in ~3% of patients [24, 25]. Hence, the poor water solubility of existing anticancer drugs poses challenges not only for oral formulations but also for intravenous formulations.

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Several attempts to address the poor water solubility of anticancer drugs have been reported, such as the use of prodrugs, polymeric nanoparticles, lipoidal microspheres, solubilizers, and nanocolloids [26-34]. However, these attempts are limited by several challenges, such as low drug loading capacity, complex physical structures, instability, potential material toxicity, altered drug distribution, and clearance [35, 36].

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The amorphous solid dispersion (ASD) is a formulation technology in which the drug, also known as the active pharmaceutical ingredient (API), is dispersed in an amorphous carrier [37]. ASDs aid the dissolution of poorly water-soluble drugs primarily by presenting the drug in an amorphous form, thereby lowering the total energy required for the solubilization of the crystalline drug [38]. ASD technology has generated tremendous benefits for therapeutically potent, poorly watersoluble anticancer drugs such as vemurafenib, regorafenib, everolimus, venetoclax, and olaparib [13, 39, 40].

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In this review paper, we discuss the causes of the poor water solubility of anticancer drugs, the application of ASDs in formulating anticancer drugs, and the benefits they offer for delivering anticancer drugs orally. We focus on anticancer drugs because their poor water solubility cannot be mitigated without compromising their potency and stability. We address the issues encountered during the oral delivery of poorly water-soluble anticancer drugs, and we discuss the role of ASDs in resolving such issues. We focus on using ASD technology not only to enhance the oral bioavailability of poorly water-soluble drugs, but also to improve the pharmacokinetic properties of such drugs and thereby improve their pharmacodynamics. The goal of this paper is to focus our literature analysis on the ability of ASDs to harness the maximum therapeutic potential of anticancer drugs. 2. Poor Water Solubility of Anticancer Drugs: Poor water solubility is an inherent property of many anticancer drugs for two main reasons. First, based on our literature review, there is seldom emphasis given on the physicochemical properties of drug candidates during anticancer drug discovery. Second, certain indispensable hydrophobic structural features are required for anticancer drug permeability, activity, and stability, which impart poor water solubility to the drug.

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Historically, one of the major pitfalls in the anticancer drug development pipeline is its negligible focus on drug disposition and pharmacodynamics [41]. The “nanomolar rule” was widely adopted in cancer drug discovery. This rule involves selecting compounds that have nanomolar potency for development [42]. This rule was based on the assumption that such compounds are required at low doses and thus would be safe and efficacious. This rule ignored a critical parameter: the physicochemical properties of these compounds, which affect their pharmacokinetics and thus their safety and efficacy [42]. Thus, compounds such as combretastatins A-4, having excellent cytotoxicity in nanomolar concentrations, were selected for development, but they eventually failed due to their poor water solubility [43, 44].

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Recently, a target-based drug discovery and development approach has been adopted for new anticancer drugs. This involves target identification and validation, followed by the development and screening of agents against their targets, followed by lead identification and optimization [45]. The protocols adopted for the screening of agents against their targets are largely unaffected by the physicochemical properties of the drug—more specifically, their water solubility. For example, in most in vitro experiments, the drugs are dissolved in organic solvents (instead of physiologically relevant aqueous solvents) and their anticancer activity on cell lines is evaluated [42, 46]. Thus, there is no selection bias against poorly water-soluble anticancer drugs in the preclinical stage. As a result, several promising anticancer drug candidates that emerged out of the drug discovery process failed during clinical development due to their poor water solubility (e.g., ABT-737, wortamanin, fenretinide, sapacitabine) [31, 47-50].

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A certain degree of hydrophobicity or lipophilicity is necessary for anticancer drugs to cross cell membranes and reach their target site of action [51]. According to Veber et al., compounds that have a topological polar surface area (TPSA) ≤ 140 have acceptable permeability [52]. However, the lower the polar surface area, the lower the water solubility. Thus, in practice, it is difficult to balance the two opposing factors of high solubility with low polarity. ABT-737, which has a lower TPSA of 131, was designed against Bcl-2 and Bcl-xL proteins, which are involved in the regulation of apoptosis. ABT-737 exhibited high potency, but it also exhibited low water solubility and therefore poor bioavailability [47, 53]. ABT-737 was then chemically modified by replacing its nitro group, which reduced its acylsulfonamide acidity. This change increased the drug’s oral bioavailability, but it also caused a decrease in potency [53]. Later, the compound ABT-263 (i.e., navitoclax), which has a TPSA of 128, was developed. This compound exhibited dissolution-limited poor oral bioavailability [53]. Eventually, compound ABT-199 (i.e., venetoclax), with a TPSA of 172, was developed. It too possessed dissolution-limited poor oral bioavailability without an enabling formulation technology [53]. Thus, in order to achieve good permeability and therapeutic activity, all the compounds designed as Bcl inhibitors were burdened with markedly poor water solubility. Many anticancer drugs require bulky hydrophobic structures such as polycyclics to exert their anticancer effects by binding to their target receptors [54, 55]. For instance, paclitaxel is a widely used anticancer drug. Paclitaxel has a bulky, fused taxane ring in its center, surrounded by several hydrophobic functional groups, which impart high lipophilicity and low water solubility to the drug

Journal Pre-proof [56]. Several attempts have been made to modify the taxane ring and to substitute hydrophilic functional groups. While these analogs imparted slight increases in water solubility, the modified drugs had less potency than paclitaxel, thereby confirming that certain hydrophobic structures were essential for paclitaxel’s antineoplastic activity [57, 58].

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Another contributor to the poor water solubility of anticancer drugs is the crystalline form of the drug. The crystalline form has advantages such as high purity and stability. However, to solubilize the crystalline form, its lattice energy barrier must be overcome, which is challenging and leads to slower drug dissolution [59]. On the other hand, the amorphous form of an anticancer drug is more water soluble, but it is also typically physically unstable, hence almost all anticancer drugs are synthesized in crystalline form. For example, bicalutamide is an anticancer drug used in the treatment of prostate cancer, and it has poor water solubility [60]. Several studies have shown that the amorphous form of bicalutamide is more water soluble than its crystalline form. However, the amorphous form of bicalutamide is highly unstable, which leads to recrystallization of the drug [60, 61]. Hence, bicalutamide is commercially available in the poorly water-soluble crystalline form. Thus, poor water solubility is an intrinsic property of several anticancer drugs.

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3. Application of ASDs to Anticancer Drugs: According to modified Noyes–Whitney equation [40, 62], (𝐶𝑠 − 𝐶) 𝑑𝐶 = 𝐷𝑆 𝑑𝑡 ℎ where dC/dt is the rate of dissolution, S is the surface area available for dissolution, D is the diffusion coefficient of the drug, Cs is the saturation solubility of the drug in the dissolution medium, C is the instantaneous concentration of the drug in the medium at time t, and h is the thickness of the diffusion boundary layer adjacent to the surface of the dissolving drug.

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According to this equation, the rate of dissolution of the drug can be increased by increasing the surface area for dissolution, which can be achieved by reducing the particle size. However, there are limitations to the minimum particle size that can be attained without encountering issues such as particle segregation and agglomeration. Other possibilities to increase the dissolution rate include modifying the surface of particles to enhance their wettability, reducing the thickness of the diffusion layer, and maintaining a high concentration gradient. Among these possible methods, the hydrodynamic changes are difficult to invoke in vivo, and sink condition maintenance also depends on the intrinsic properties of the drug [63]. One possibility for increasing the dissolution rate—i.e., increasing the saturation solubility of the drug or its apparent aqueous solubility—appears to be most promising method, and it is attainable by reducing particle size and by adopting an ASD technology [63, 64]. The term solid dispersion was first defined as “… the dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting (fusion), solvent, or meltingsolvent method” [65]. ASDs are essentially solid glass solutions in which the API is dissolved in an amorphous carrier [37]. The amorphous form of the drug exhibits a disordered structure

Journal Pre-proof compared to its crystalline form, and it possesses higher free energy, which leads to higher apparent aqueous solubility and faster dissolution of the drug [66]. However, the neat amorphous form of the drug itself tends to be highly unstable and shows a greater tendency to recrystallize [67]. Thus, neat amorphous forms of drugs are rarely used. ASDs kinetically stabilize the amorphous form of the drug by dispersing the drug in an amorphous matrix composed of polymers or oligomers. Figure 1 illustrates the process of solubilization of anticancer drugs in their crystalline state, their neat amorphous state, and in ASD form. This process involves a pre-step to convert the crystalline drug to a non-crystalline form of the drug and three basic steps: (1) solvent cavitation, (2) solvation, and (3) maintenance of solvation.

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In the pre-step, the crystal lattice of a poorly water-soluble anticancer drug in its crystalline state must be disrupted to convert the compound to a non-crystalline drug. This is an endothermic step that requires high energy to disrupt the crystalline lattice. The non-crystalline state of the drug is highly physically unstable and tends to revert to its crystalline state. There is no significant prestep for neat amorphous anticancer drugs, since these drugs are already in an amorphous form. However, neat amorphous drugs are also highly unstable and have a greater tendency to recrystallize. Similarly, no significant pre-step is involved for the solubilization of anticancer drugs in an ASD. Moreover, the physical form of a drug in an ASD is stabilized by polymers/oligomers, which prevent recrystallization of the drug.

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After the pre-step, the first step of solvent cavitation involves the creation of space in the solvent to host the drug molecules. This is also an endothermic step. The rate and extent of solvent cavitation is higher for an ASD compared to a crystalline or neat amorphous drug. This is because the hydrophilic polymers/oligomers aid in the reduction of surface tension between the drug and solvent, thereby making larger cavities in the solvent more quickly.

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After solvent cavitation, the next step involves the solvation of the drug molecules into the solvent, thereby leading to drug solubilization. This is an exothermic step. For crystalline anticancer drugs, only limited amounts of the drug dissolve, corresponding to or slightly greater than its equilibrium solubility. For neat amorphous anticancer drugs and for anticancer drugs in an ASD, more of the drug dissolves, leading to a supersaturated solution. The final step involves maintenance of the solvated state of the drug. For crystalline drugs, precipitation of the dissolved drug above its equilibrium solubility occurs. For neat amorphous anticancer drugs, the maintenance of their supersaturated solvated state is momentary, and the drug undergoes rapid precipitation. On the other hand, for anticancer drugs in an ASD, the polymers/oligomers prevent drug precipitation and thereby maintain the supersaturation of the solvated drug.

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Figure 1. Schematic representation of the process of solubilization of anticancer drugs in their crystalline state, neat amorphous state, and in an ASD. Reproduced with permission. The schematic is modified with respect to anticancer drug states and solubilization steps [38].

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There are several methods for manufacturing ASDs based on heating (e.g., hot melt extrusion) or based on solvents (e.g., spray-drying, freeze drying, thin-film freezing, coprecipitation, electrospinning) [39, 68-73]. The heating-based methods may not be suitable for thermolabile drugs. The solvent-based methods are limited by the solubility of the drug in organic solvents. In addition, solvent-based methods are often associated with economic, environmental, and safety concerns. We have previously reported that KinetiSol® is a solvent-free, thermokinetic method for manufacturing ASDs, and this method is suitable for several drugs, including thermolabile drugs and drugs that have limited solubility in organic solvents [74-77]. 4.

Benefits of Oral Administration of Anticancer Drugs and Current Market Scenario: One might argue that the parenteral administration of anticancer drugs should be the preferred route, since parenteral administration circumvents several challenges associated with the oral administration of poorly water-soluble drugs. However, the abundant benefits of oral administration tend to refute this argument.

4.1. Benefits of Oral Administration of Anticancer Drugs: Administering anticancer drugs orally addresses unmet personnel needs, unmet pharmacoeconomic needs, as well as unmet pharmacological needs. Table 1 illustrates the benefits of administering anticancer drugs orally.

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4.2. Current Market Scenario for Oncology Drug Products: We performed a survey (See Appendix 1 for details) of the oncology drug products approved by the US FDA between January 2000 and September 2018. We then categorized these drugs based on their route of administration [95, 96]. Figure 2 illustrates the results of the survey. We find that among the 167 oncology drug products surveyed, about 42.8% were intravenously administered. Thus, there are enormous opportunities for developing oral counterparts for currently intravenously administered anticancer drugs, thereby making their therapy more convenient and economic. Anticancer drugs such as vinorelbine, idarubicin, etoposide, and paclitaxel have undergone the beneficial ‘intravenous to oral switch’ [82, 97]. Yet, there are some shortcomings with their therapies, such as high intersubject pharmacokinetic variability and toxicity, which could be resolved by ASDs.

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Figure 2. Oncology drug products approved by the US FDA between 2000 and 2018, categorized based on route of administration. Sawicki et al. surveyed 72 oral anticancer drugs and categorized them based on their formulation approach and BCS class. Figure 3 illustrates the types of formulation approach adopted for the surveyed 72 oral anticancer drugs. They found that 65% of the drugs surveyed were poorly water soluble and belonged to BCS Class II or IV . Yet, only 4% of the drugs surveyed were formulated as ASDs, and the majority of them were formulated as physical mixtures—i.e., the neat crystalline drugs were dry mixed or granulated with pharmaceutical excipients [13]. This suggests that a majority of orally administered anticancer drugs are suboptimally delivered, which indicates a substantial opportunity for harnessing their complete therapeutic potential through the application of ASD technology.

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Figure 3. Oral anticancer drugs, categorized based on type of formulation. “Reproduced from [13]. Reproduced with permission”.

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From the above surveys, we can conclude there is a tremendous pool of existing approved and marketed oncology drug products that could benefit from ASD technology by converting their existing intravenous formulations into oral formulations or improving their current oral formulations.

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5. Challenges and Consequences Associated with Oral Administration of Poorly Water-soluble Anticancer Drugs: Based on the above analysis and discussion, it is evident that the oral administration of anticancer drugs is beneficial and there is a need for improved anticancer drug formulations. In order to develop superior formulations for harnessing more of the therapeutic potential of anticancer drugs, it is imperative to understand the possible challenges that could arise. In addition to poor water solubility, several other challenges are associated with administering poorly water-soluble anticancer drugs orally [91]. 5.1. Drug-Related Challenges: 5.1.1.Solid State: For an oral anticancer drug to be effective, it must first dissolve in the gastrointestinal tract [98, 99]. As mentioned earlier, many anticancer drugs have poor water solubility, which limits their dissolution in gastrointestinal tract. The equilibrium solubility of anticancer drugs is not only dependent on interactions between the drug and solvent but also on intermolecular interactions within the solid state of the drug [100]. Most anticancer drugs are available in their crystalline state, which has strong intermolecular interactions. As discussed above, these intermolecular interactions lead to

Journal Pre-proof strong crystal packing, so they must be disrupted in order to solubilize the drug. Thus, crystal packing in the solid state of anticancer drugs is a major challenge that affects their solubility. Anticancer drugs can exist in multiple crystalline phases called polymorphs. These polymorphs have the same chemical composition but different internal structures [101]. Solvates or hydrates are formed when one or more solvents or water molecules are incorporated into a drug crystal lattice [102]. Thus, anticancer drugs can exist as different polymorphs, solvates, or hydrates in their solid state, which can affect their stability and solubility [103].

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For example, axitinib, a kinase inhibitor, is used in the treatment of renal cell carcinoma [104]. Structurally, it has strong molecular flexibility, thus it can exist in 60 solvates, polymorphs of solvates, and five anhydrous forms, all of which have varied stability and solubility [105]. Depending on the method of synthesis, dasatinib can crystallize in several different solvate forms, each with varied solubility, thereby exacerbating the issue of its poor water solubility [106, 107]. Bicalutamide can exist in polymorphic Forms I and II [108, 109]. While Form I of bicalutamide has higher stability, its unstable Form II is 2.4 times more soluble than Form I [108-110]. 6-mercaptopurine, an anticancer drug used in the treatment of leukemia, can exist in different polymorphic forms that have varied solubility [111-113]. Sorafenib tosylate exhibits polymorphism, and it can crystallize into three different polymorphs (i.e., Mod I, Mod II, and Mod III). Mod I is present in the corresponding commercial product Nexavar® [114]. Also, depending upon its method of preparation, Sorafenib tosylate can crystalize into different solvate forms that have varied solubility and chemical stability [115, 116]. It had been demonstrated that Form II of sorafenib tosylate has better solubility than Form I, but it was metastable and thus physically unstable in its neat form [117]. ARRY-380, also known as irbinitinib or tucatinib, is a selective herb2 inhibitor under investigation for treatment of breast cancer [118, 119]. During its polymorph screening, 29 crystal forms were discovered [118]. On further investigation of its seven solvate forms, it was found that the ethanol and tetrahydrofuran solvates of ARRY-380 have poor solubility. However, they were thermodynamically stable and hence used for further development [118, 120]. Ceritinib is a BCS Class IV drug used in the treatment of ALK-positive metastatic non-small cell lung cancer [121]. Its commercial formulation Zykadia® contains Form I/Form A of ceritinib [122]. Chennuru et al. discovered two novel forms of ceritinib: Form II, which is a hydrate form, and Form III, another polymorph. Form II and Form III have aqueous solubility of 0.9 mg/mL and 0.1 mg/mL, respectively, while Form I has an aqueous solubility of only 0.001 mg/mL [121]. Gefitinib is a kinase inhibitor used in the treatment of non-small cell lung cancer [123]. It exhibits polymorphism, with Form II being physically unstable [123, 124]. Vemurafenib is a potent kinase inhibitor used in the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation [125, 126]. During its first clinical trial, 100 mg and 300 mg capsules containing the crystalline Form I of vemurafenib were used. It was noted that Form I of vemurafenib slowly transformed into Form II, and the observed bioavailability was low during initial clinical trials [39, 125]. It was later discovered that

Journal Pre-proof Form I of vemurafenib was thermodynamically unstable, while Form II was thermodynamically stable but had lower aqueous solubility [125]. Hence, further development using Form II of vemurafenib was conducted. Thus, poorly water-soluble crystalline anticancer drugs can exhibit polymorphism. In general, if a metastable crystalline form of an anticancer drug is used, it has the propensity to transition into a thermodynamically stable form and thereby exacerbate the issue of poor water solubility.

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5.1.2.Ionization: In addition to crystallinity, the solubility of sparingly soluble ionizable anticancer drugs is also dependent on the pKa of the drug and the pH of the gastrointestinal tract [127-129]. The pH, which varies throughout the gastrointestinal tract, is affected by factors such as bile secretion, pancreatic secretions, food content, other medications, and disease state [130, 131]. Overall, under fasting conditions, the pH of the stomach is between 1.0 and 2.5, the pH of the duodenum is between 5.8 and 6.5, and the pH of the jejunum is between 4.4 and 6.5 [132, 133]. Under non-fasting conditions, the pH of the stomach is between 4.3 and 5.4, the pH of the duodenum is between 3.1 and 6.7, and the pH of the jejunum is between 6.8 and 7.8 [133]. It is important to note that there is high variability in the reported pH values for the gastrointestinal tract. In general, the solubility of sparingly soluble acidic anticancer drugs decreases with a decrease in pH, since the drug largely remains unionized. The reverse is true for sparingly soluble basic anticancer drugs. Most anticancer drugs are absorbed from the small intestine; therefore, any changes in intestinal pH affects the ionization of the drug and thus its solubility and bioavailability [91]. It is also important to note that although the ionized form of drugs are more soluble, they are less permeable through nonpolar membranes [134]. Several sparingly water-soluble anticancer drugs have multiple ionizable groups, and they show pH-dependent solubility. For example, lapatinib, a kinase inhibitor, is used in the treatment of breast cancer. Its solubility is 0.007 mg/mL in water and 0.001 mg/mL in 0.1 N HCl at 25 °C [135]. Dasatinib monohydrate is another kinase inhibitor used in the treatment of chronic myeloid leukemia. It is available as a crystalline white powder that exhibits significantly pHdependent water solubility ranging from 18.4 mg/mL at pH 2.6 to 0.008 mg/mL at pH 6.0 [136]. Tamoxifen citrate, used in the treatment of breast cancer, has a solubility of 0.5 mg/mL in water and 0.2 mg/mL in 0.02 N HCl at 37 °C [137, 138]. Vismodegib, the first Hedgehog signaling pathway inhibitory agent used in the treatment of skin cancer, shows significant pH-dependent solubility ranging from 1 mg/mL at pH 1.0 to 0.0001 mg/mL at pH 7.0 [139]. Nilotinib is a potent kinase inhibitor used in the treatment of patients who are in the chronic and accelerated phases of Philadelphia chromosome‐positive chronic myeloid leukemia [140]. This drug is used as a hydrochloride monohydrate salt having pKa1 ~ 2.1 and pKa2 ~ 5.4 [140]. Nilotinib hydrochloride monohydrate is slightly soluble at pH 1 and practically insoluble at pH ≥ 4.5 [140]. Nintedanib, an anticancer drug used in the

Journal Pre-proof treatment of non-small cell lung cancer, also shows significant pH-dependent solubility, from 10 mg/mL at pH 2.0 to a dramatically decreased 0.001 mg/mL at pH 6.0 [141]. Thus, depending on the degree of ionization, an anticancer drug that is sparingly soluble at a given pH can become highly insoluble at another pH. Hence, pH-dependent solubility is another challenge associated with the oral administration of ionizable, poorly watersoluble anticancer drugs.

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5.1.3.Stability: The stability of anticancer drugs in the gastrointestinal content is a prerequisite for optimum delivery. The anticancer drug could undergo chemical hydrolysis, which is a degradation due to gastric juices containing hydrogen ions, bicarbonates, and chlorides [133, 142].

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For example, chlorambucil, an alkylating agent used in the treatment of Hodgkin’s lymphoma, was found to undergo extensive degradation at higher pH and lower chloride concentrations in human gastric juices. It was found that 100% chlorambucil degraded over 180 min between pH 5.5 and 7.6 and chloride ion concentrations of 91–67 mmol/L [143]. Also, doxorubicin, a cytotoxic drug, was found to undergo gastric acid-catalyzed hydrolysis. It was estimated that in patients with a gastric pH of 1 and a gastric emptying time of 4 h, about 45% of the ingested doxorubicin would degrade in the patient’s stomach [144]. Etoposide, a topoisomerase inhibitor, is known to undergo degradation in gastric fluids [145, 146]. During the development of the stability-indicating HPLC method for 4-(3,5-bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid, a new anticancer drug under investigation, it was found that the drug underwent significant degradation at pH ≤ 3.5 [147]. This suggests potential instability of this drug in gastric media. BMS-753493 is a novel folate-targeted candidate being developed for the treatment of cancer. It was most stable between pH 6.0 and 7.0, and it showed instability at lower and higher pH values at 25 °C and 40 °C [148]. Thus, the instability of BMS-753493 at lower pH is a potential challenge for developing its oral formulation. Other factors (e.g., enzymatic degradation, food contents) also affect the stability of anticancer drugs in the gastrointestinal tract. These factors are discussed in subsequent sections. 5.1.4.Drug–drug interaction: Co-therapy is common during cancer treatment, thus the risk of potential drug–drug interactions is high [149]. The prevalence of significant drug–drug interactions is higher among oral anticancer drugs than among intravenous anticancer drugs [149, 150]. Since we focus on oral administration in this paper, we discuss drug–drug interactions that have a negative impact on the oral absorption of anticancer drugs. Sometimes, other medications that are administered along with anticancer drugs may hinder the anticancer drugs’ oral bioavailability by affecting its solubility or permeability (a) through altering the pH of the gastrointestinal tract, (b) by competing for transporters, or (c) by modifying metabolic enzyme activity [151].

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As discussed above, several anticancer drugs exhibit pH-dependent solubility. Acidreducing drugs, such as proton pump inhibitors, elevate gastric pH, thereby reducing the solubility of weakly basic anticancer drugs and thus reducing their oral bioavailability. From a clinical data survey of drug–drug interactions between anticancer drugs and proton pump inhibitors, it was found that the magnitude of the drug–drug interactions was largest for compounds whose in vitro solubility varied over the range of pH 1–4 [152]. Erlotinib, a kinase inhibitor, is used in the treatment of non-small cell lung cancer. In a study, it was found that the trough concentrations of erlotinib were significantly diminished when high doses of intravenous pantoprazole, a proton pump inhibitor, was administered simultaneously [153]. It was reported that when famotidine, an H2-receptor antagonist was administered 2 h post dasatinib, no impact on the exposure of dasatinib was seen. However, when the next dose of dasatinib was administered (i.e., 10 h post famotidine dose), a 60% reduction in AUC0–12 and Cmax for dasatinib was observed [154]. It was concluded that elevation of gastric pH by famotidine reduced the solubility of dasatinib and thus reduced its bioavailability [154]. Gefitinib also exhibits pH-dependent solubility [123]. In a retrospective study involving non-small cell lung cancer patients taking gefitinib, it was found that patients taking proton pump inhibitors had lower AUC0–24 (median value 8,542 ng.hr/mL) compared to AUC0-24 (median value 13,103 ng.hr/mL) for patients taking only gefitinib [155]. Bosutinib, a kinase inhibitor used in the treatment of leukemia, shows pH-dependent solubility [156]. About a 38% reduction in Cmax and a 24% reduction in AUC were observed for bosutinib when it was coadministered with lansoprazole [156]. Pazopanib is a BCS Class II anticancer drug used in the treatment of soft-tissue sarcoma and renal cell carcinoma [157, 158]. It also exhibits pH-dependent solubility and is practically insoluble at pH > 4 [158]. A retrospective study evaluated treatment outcomes of patients with soft-tissue sarcoma who were treated with pazopanib. It was observed that for patients taking pazopanib together with concomitant gastric acid suppressive agents, the median progression free survival (2.8 vs 4.6 months) and median overall survival (8.0 versus 12.6 months) were significantly lower than for patients who were taking only pazopanib [158]. It was suspected that long-term use of gastric acid suppressive agents leads to elevation of gastrointestinal pH. This leads to poor solubility of pazopanib, hence poor bioavailability and ultimately poor therapeutic outcomes [158]. It is interesting to note that another retrospective study involving renal cell carcinoma patients found that the concomitant use of pazopanib with gastric acid suppressive agents was not associated with progression-free survival or overall survival [157]. Abiraterone acetate is a prodrug used in the treatment of prostate cancer [159]. It is converted into its active metabolite, abiraterone, predominantly pre-systemically via esterases [160, 161]. In a pharmacokinetic study in dogs, it was observed that coadministration of orlistat with abiraterone acetate led to a decrease in plasma concentrations of abiraterone [160]. This is because orlistat inhibits esterases, thereby reducing the conversion of abiraterone acetate into abiraterone, thus reducing

Journal Pre-proof abiraterone supersaturation and absorption [160]. This drug–drug interaction between abiraterone acetate and orlistat requires further investigation. Regorafenib is a kinase inhibitor used in the treatment of colorectal cancer [162]. Bile salt sequestering drugs such as cholestyramine and Cholestagel can form insoluble complexes with regorafenib, thereby reducing its solubility and in turn reducing its absorption and reabsorption [162, 163]. This further demonstrates that interactions between poorly water-soluble anticancer drugs and other drugs can negatively impact their solubility or permeability, which in turn alters the pharmacokinetics of poorly water-soluble anticancer drugs.

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5.2. Physiology-Related Challenges:

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5.2.1.Transmembrane efflux of drugs: Certain proteinaceous transporters are located on the intestinal membrane, and they act as efflux pumps. These efflux pumps significantly reduce the oral bioavailability of anticancer drugs. When anticancer drugs successfully dissolve and permeate the membrane, these efflux pumps eject the anticancer drugs back into the intestinal lumen, so the anticancer drugs are ultimately eliminated through excretion.

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The major efflux transporters belong to the ATP binding cassette (ABC) transporters family, and several anticancer drugs act as substrates for these transporters [164, 165]. The major efflux transporters of the ABC family include P-glycoprotein (P-gp, ABCB1), a breast cancer resistance protein (BCRP, ABCG2), and multidrug resistance-associated proteins (MRP2 , ABCC2) [166]. They are localized to barrier tissues of the body, such as the intestine, liver, kidneys, blood-brain barrier, and placenta. Table 2 lists the poorly water-soluble anticancer drugs that are substrates for major efflux pumps located on the intestinal membrane. The P-glycoprotein transporter is one of the most widely studied efflux pumps. It has broad substrate specificity and is also known to act synergistically with cytochrome P450 enzymes [167]. By effluxing absorbed anticancer drugs back into intestinal lumen for reabsorption, P-gp efflux pumps permit significant time for cytochrome P450 enzymes to metabolize anticancer drugs, thereby significantly reducing their oral bioavailability [167]. One study found that the oral bioavailability of etoposide, a cytotoxic drug, was reduced by 26% due to P-gp efflux pumps [168]. Additionally, due to variations in P-gp efflux pump levels in patients, etoposide demonstrated high pharmacokinetic variability [169]. In preclinical studies in P-gp knockout mice, the apparent oral bioavailability of paclitaxel and docetaxel were increased by ~24% and ~19%, respectively as compared to the wild-type mice [170]. One study observed that the oral bioavailability of a topoisomerase inhibitor, topotecan, was increased from 40% to 97% by the coadministration of a BCRP inhibitor [171]. It is interesting to note that while the oral bioavailability of several anticancer drugs

Journal Pre-proof is reduced because they act as substrates for efflux pumps, these anticancer drugs can also enhance the oral bioavailability of other drugs that have a comparatively lower affinity for efflux pumps [172]. This raises the possibility of a substantial risk of drug–drug interaction between different coadministered anticancer drugs, leading to a reduced oral bioavailability of one drug and an enhanced oral bioavailability of another drug.

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5.2.2.Pre-systemic metabolism: The pre-systemic metabolism involves metabolism in the gastrointestinal lumen, the brush border metabolism, the intracellular metabolism, and the first-pass metabolism [164]. Enzymes such as amylases, lipases, esterases, and bacterial enzymes secreted by gut flora are present in the gastrointestinal lumen and are responsible for metabolizing anticancer drugs in the gastrointestinal tract [164, 175]. Brush border metabolism mainly occurs in the proximal small intestines and is caused by enzymes such as alkaline phosphatase, sucrase, and peptidases [176]. Intracellular metabolism in the gut is caused by extrahepatic microsomal enzymes of the cytochrome P450 3A family, mainly CYP 3A4 [177]. Thus, these enzymes are responsible for metabolizing the anticancer drugs before or during their absorption. Once the anticancer drugs are absorbed from the gastrointestinal tract, they can enter the liver via the hepatic portal vein. In the liver, a fraction of these absorbed drugs are metabolized by a plethora of enzymes. This is known as first-pass metabolism [164]. This means that even before an anticancer drug reaches systemic circulation, it can undergo metabolism that leads to the formation of inactive metabolites and thus low oral bioavailability. Some examples of poorly water-soluble anticancer drugs that undergo extensive pre-systemic metabolism include ibrutinib, flutamide, erlotinib, gefitinib, paclitaxel, lapatinib, tamoxifen, docetaxel, vincristine, vinblastine vindesine, vinorelbine, etoposide, sorafenib, sunitinib, imatinib, and everolimus [178-187]. Also, enzymes such as peptidases pose a significant challenge for the oral delivery of peptide anticancer drugs such as buserelin, triptorelin, gonadorelin, nafarelin, and leuprolide [188, 189]. Additionally, different levels of expression of metabolic enzymes in healthy subjects compared to cancer patients causes a vast amount of variability in pharmacokinetic data, specifically for anticancer drugs [190]. Also, polymorphism in genes that code for these metabolic enzymes causes high intersubject pharmacokinetic variability among anticancer drugs [191]. Since anticancer drugs act as substrates for metabolic enzymes, they have a high potential for drug–drug interactions with strong enzyme inducers and inhibitors, thereby affecting their pharmacokinetics. For example, cabozantinib is a kinase inhibitor used in the treatment of thyroid cancer [192]. The enzyme inducer rifampin reduces the AUC of cabozantinib by 77% [192]. It is important to note that while pre-systemic metabolism reduces oral bioavailability for several anticancer drugs, it also helps activate some anticancer prodrugs such as abiraterone acetate and irinotecan [161, 193]. Hence, pre-systemic metabolism is a major challenge that affects the absorption of poorly watersoluble anticancer drugs, thereby leading to reduced bioavailability and increased pharmacokinetic variability.

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5.2.3.Transporter saturation: There are two main classes of transporters in the gastrointestinal tract: the solute carrier (SLC) family of transporters and the ATP-binding cassette (ABC) transporters [174]. The SLC transporters mainly play a role in drug absorption, while ABC transporters are mainly responsible for drug efflux, and these are discussed above. The most important SLC transporters on the intestinal membrane include the organic anion transporting polypeptide (OATP) family of transporters, the peptide transporter 1 (PEPT1), and the apical sodium/bile acid co-transporter (ASBT) [194].

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5.3. Other Challenges:

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The saturation of these compounds responsible for transporting some anticancer drugs into systemic circulation can lead to reduced bioavailability of anticancer drugs at high doses. Transporter saturation is also a cause of nonlinear pharmacokinetics. For example, melphalan is an anticancer drug with water solubility of < 1 mg/mL, and it is absorbed from the gastrointestinal tract via the amino acid transport system. At high doses of melphalan (> 0.75 mg/kg), significant reduction in AUC is observed due to the saturation of the amino acid transporters [195]. 5-aminolevulinic acid is used in the treatment of several malignant and premalignant conditions [196]. It is transported by PEPT1, and it has demonstrated concentration-dependent jejunal uptake in perfusion studies [196]. PEPT1 also plays a role in the intestinal uptake of peptide-like anticancer drugs [197]. Interestingly, the saturation of the aforementioned efflux drug transporters can increase the bioavailability of anticancer drugs at high doses [198]. Thus, transporter saturation can have a significant effect on the pharmacokinetics of substrate poorly water-soluble anticancer drugs, leading to dose-exposure nonlinearity.

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5.3.1.Prandial state: Anticancer drug solubility as well as absorption can be affected by the prandial status. For instance, in non-fasting conditions, the pH of the stomach may increase and thus alter anticancer drugs’ solubility and thereby their oral bioavailability. The composition of food (e.g., a high-fat meal) may enhance the solubility of a lipophilic drug and thereby increase its oral bioavailability. Under fasting conditions, gastric motility could be higher, and this can lead to anticancer drug formulation elimination, before drug release, dissolution, and absorption. Also, certain components of food (e.g., flavonoids) may interact with anticancer drug transporters and metabolizing enzymes thereby affecting their bioavailability. Certain foods (e.g., grape fruit juice, wine, tea) demonstrate prominent food–drug interaction with anticancer drugs [199, 200]. Table 3 describes examples of poorly water-soluble anticancer drugs that demonstrate prominent food effects on their pharmacokinetics. It is evident from Table 3 that prandial state (fed versus fasted) and meal content can have considerable positive, negative, and even mixed effects on the pharmacokinetics of poorly water-soluble anticancer drugs.

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Such food effects can make dosing-drug exposure unreliable, thereby warranting limitations such as fasting for certain periods or avoidance of certain meals while taking poorly water-soluble drugs orally. This can further affect dosage regimen designs. For instance, if a drug requires three hours of fasting, administering such a drug three times daily is not practically possible. Also, patient adherence to medication can be negatively impacted. Thus, the effect of prandial state on the pharmacokinetics of poorly watersoluble anticancer drugs is a major challenge for delivering them orally.

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5.3.2.Patient/Oncologist Related Challenges: Other factors such as the patient’s age, patient’s comorbid condition, patient’s adherence, oncologist’s experience, and oncologist’s preferences may prove to be challenging for the oral administration of anticancer drugs [14, 216, 217]. Aging can lead to physiological changes such as reduction in enzyme activity, which may have prominent effects on anticancer drug pharmacokinetics [217]. Certain co-morbid conditions can alter the physiology of the gastrointestinal tract and hepatic function, thus affecting the bioavailability of the anticancer drug. Given et al. reported that surveyed cancer patients had 1–4 pills per day for oral cancer medications, in addition to 10–11 medications for their comorbid condition [218]. Such high pill burden can affect a patient’s adherence to the treatment regimen and thus affect the therapeutic outcome. Some oncologists may prefer IV anticancer drugs based on prior specific experiences and thus may avoid prescribing oral anticancer drugs. These miscellaneous challenges pose hurdles for the oral administration of poorly water-soluble anticancer drugs.

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It is apparent from the above discussion that poorly water-soluble anticancer drugs do not face one or two unique challenges, but rather a multitude of interdependent challenges. This is true not only for approved poorly water-soluble anticancer drugs such as abiraterone, axitinib, erlotinib, and lapatinib, but also for newer anticancer drugs under investigation. For example, TAK-117 (also known as MLN1117 or serabelisib) is a new anticancer drug under investigation by Takeda for the treatment of advanced solid malignancies [219]. TAK-117 faces challenges such as poor water solubility, polymorphism, pH-dependent solubility, drug interaction with lansoprazole, and food effects; all of which change the pharmacokinetics of the drug [220, 221]. A complex interplay of these challenges leads to five major pharmacokinetic or pharmacodynamic consequences, as illustrated in Figure 4, which hinder the therapeutic outcomes of orally administered poorly water-soluble anticancer drugs.

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Figure 4. Challenges and consequences associated with the oral administration of poorly watersoluble anticancer drugs.

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6. Alleviating the Consequences through ASDs: ASDs can alleviate the consequences associated with the oral administration of poorly watersoluble anticancer drugs as follows:

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Figure 5. Role of ASDs in alleviating the challenges and consequences associated with the oral administration of poorly water-soluble anticancer drugs, thereby leading to improved oncological therapeutic outcomes. [ASD–amorphous solid dispersions, MTC-minimum toxic concentration, MEC-minimum effective concentration, Cmax = maximum plasma drug concentration, Cmin = minimum plasma drug concentration, AUC = area under the plasma drug concentration time curve, t = duration of drug exposure.] 6.1. Enhancing Oral Bioavailability: Oral bioavailability is defined as the fraction of an orally administered drug that reaches systemic circulation. It can be determined by comparing the area under the curve (AUC) (of the plot of plasma drug concentration versus time) of an oral dose to the AUC of an intravenous dose [222]. ASD formulations can enhance the oral bioavailability of poorly water-soluble anticancer drugs when compared to conventional oral formulations such as physical mixtures of drugs and excipients (Figure 5a). One of the major factors contributing to the poor oral bioavailability of anticancer drugs is their low water solubility. ASDs increase the rate of anticancer drug dissolution by increasing the apparent aqueous solubility of the drug in the gastrointestinal media [223]. Docetaxel is a

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microtubule inhibitor used in the treatment of a variety of cancers such as prostate cancer, breast cancer, lung cancer, gastric cancer, and head–neck cancer [224]. Currently, docetaxel is available as an injection for intravenous infusion, which is associated with acute hypersensitivity reactions [225]. Hence, an oral formulation of docetaxel is desirable. Docetaxel is practically insoluble in water (solubility < 0.1 mg/mL), is highly lipophilic (LogP ~4.2) and has bulky hydrophobic groups, all of which contribute to its poor oral bioavailability [224]. Lim et al. developed an ASD of docetaxel with Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) and increased docetaxel’s solubility in 0.1 M, pH 6.8 phosphate buffer by 93-fold, from 3.9 ± 0.2 µg/mL for neat crystalline docetaxel to 362.93 ± 11.01 µg/mL for a binary solid dispersion of docetaxel and Soluplus® [226]. Sawicki et al. reported the development of an ASD of paclitaxel or docetaxel with Povidone K30 (polyvinylpyrrolidone-PVPK30) and sodium dodecyl sulfate (SDS) at a 1:9:1 weight ratio [92, 227, 228]. These solid dispersions were reported to enhance the solubility of paclitaxel and docetaxel by 100 times and 40 times, respectively, compared to the crystalline forms of the drugs [227]. Chen et al. developed an emulsifying ASD of docetaxel that enhanced its solubility and dissolution by 34.2-fold and 12.7-fold, respectively, compared to its crystalline form [229]. Piao et al. developed an ASD of paclitaxel with hydroxy propyl methyl cellulose acetate succinate (HPMCAS) and porous silicon dioxide [230]. This solid dispersion enhanced the solubility of paclitaxel and its bioavailability in rats, by 7-fold compared to neat paclitaxel [230]. Andrews et al. developed an ASD of bicalutamide with PVP K25 at drug:polymer weight ratios of 1:10, 2:10, and 3:10 [231]. They observed that physical mixture (1:10 w/w) enhanced the dissolution of bicalutamide by 2.31-fold compared to crystalline bicalutamide alone [231]. These ASDs were able to enhance the dissolution of bicalutamide by 7.53-, 8.05-, and 8.93fold compared to crystalline bicalutamide, with an increasing concentration of PVP K25 [231]. Ren et al. reported development of an ASD of bicalutamide with PVP K30, and they saw similar trends in dissolution—i.e., the dissolution of ASD with higher PVP K30 > ASD with lower PVP K30 > physical mixture with higher PVP K30 > crystalline bicalutamide [232]. Several other studies have reported the development of solid dispersions of bicalutamide that exhibit reduced crystallinity, leading to improved apparent aqueous solubility of bicalutamide [233-236]. ASDs of ceritinib with polymers such as hydroxy propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), vinylpyrrolidone-vinyl acetate–Copovidone (PVPVA) and PVP have been reported to enhance the dissolution and bioavailability of ceritinib [237, 238]. Enzalutamide is a poorly water-soluble anticancer drug used in the treatment of castration-resistant prostate cancer [239]. Wilson et al. developed a binary ASD of enzalutamide with HPMCAS and PVPVA at drug loadings of 10% and 50% w/w. Interestingly, in this case, the dissolution enhancement of enzalutamide showed a trend of 50:50 %w/w enzaluatmide:HPMCAS ASD > 10:90 %w/w enzalutamide:PVPVA ASD > 50:50 %w/w enzalutamide:PVPVA ASD >>> 10:90 %w/w enzalutamide:HPMCAS ASD > crystalline enzalutamide [239]. It was inferred that 10:90 %w/w enzalutamide:HPMCAS ASD showed lower dissolution enhancement despite higher polymer content because it quickly precipitated into the crystalline form of the drug during dissolution. The 10:90 %w/w enzalutamide:PVPVA ASD showed slower precipitation into amorphous aggregates during dissolution, and it showed the highest bioavailability enhancement in rats for enzalutamide, ~7-fold [239]. Shepard and Morgen developed a ternary ASD of erlotinib with poly[(methyl methacrylate)-co(methacrylic acid)]

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(Eudragit® L100 ) and HPMC. This ASD enhanced the dissolution of erlotinib and enhanced its bioavailability more than 10-fold [240]. Shah et al. demonstrated the ability of solid dispersion of etoposide with polyethylene glycol (PEG), in which etoposide in the amorphous state enhanced the dissolution rate of etoposide by 42-fold [241]. Song et. al. developed ASDs of the weakly basic drugs gefitinib and lapatinib with polystyrene sulfonic acid. This led to enhanced dissolution of both drugs [242]. Herbrink et al. developed an ASD of nilotinib with Soluplus®, which enhanced the solubility of nilotinib 630-fold compared to crystalline nilotinib in simulated intestinal fluids [243]. Oridonin is a poorly water-soluble drug that has marked anticancer effects [244]. Li et al. developed an ASD of oridonin with PVP K17 and were able to enhance its dissolution and bioavailability in dogs by 26-fold [244]. ASDs of tamoxifen citrate that enhance its dissolution and bioavailability have been reported [245, 246].

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ASDs can eliminate poor water solubility that occurs due to polymorphic transitions of the drug. This is because the crystalline structure of the drug is disrupted, and the drug is converted into an amorphous form where it is stabilized by polymers or oligomers, thereby eliminating the possibility of transition into other polymorphs of the drug. Szafraniec et al. spray-dried neat bicalutamide and a mixture of bicalutamide with PVP [247]. While spray-dried neat bicalutamide showed polymorphic transitions in its solid state, the spray-dried bicalutamide-PVP mixture was stable, with bicalutamide being dispersed in an amorphous state in the PVP matrix [247]. Tres et al. prepared ASDs of bicalutamide with Kollidon VA 64 (Copovidone) at drug loadings of 5% w/w and 50% w/w [248]. As in previous cases, they observed that the dissolution of bicalutamide increased with higher concentrations of the polymer. After further investigation, they found that in ASDs loaded with 5% bicalutamide, the rate of drug and polymer dissolution was similar. However, in ASDs loaded with 50% bicalutamide, the polymer dissolved at a faster rate than the drug, leading to a rich layer of amorphous bicalutamide, which precipitated to its polymorphic Form I and Form II, thereby lowering the overall dissolution [248]. These studies emphasized the importance of polymers and their concentration in ASDs in the prevention of polymorphic transitions of poorly water-soluble anticancer drugs, thereby enabling maximum stability and solubility and thus maximum bioavailability. Although the focus of this paper is on poorly water-soluble anticancer drugs, it is important to recognize that, in addition to poor water solubility, several other factors hinder the oral bioavailability of poorly water-soluble anticancer drugs. Thus, it is imperative to discuss the role of ASDs in removing barriers to oral bioavailability that go beyond poor water solubility. Another challenge leading to the low oral bioavailability of poorly water-soluble anticancer drugs is their instability in gastrointestinal media. Through a repurposing strategy, it was found that clarithromycin, an antibiotic, has promising anticancer activity [249]. However, its use in oncology is challenging, since it has poor oral bioavailability due to poor solubility at neutral intestinal pH, and high solubility coupled with high degradation in gastric pH [250, 251]. Pereira et al. proposed an ASD of clarithromycin with a hydrophobic cellulose derivative, cellulose acetate adipate

Journal Pre-proof propionate (CAAdP) polymer. They demonstrated the effect of the ASD in simultaneously enhancing the solubility of clarithromycin and preventing its degradation in gastric juices [252]. Poor oral bioavailability of anticancer drugs due to their interaction with other drugs can be avoided by emphasis on drug–drug interaction studies during early clinical development [253]. Moreover, the drug–drug interactions discussed above, which lead to reduced solubility of anticancer drugs due to gastrointestinal pH changes, can be avoided by the addition of acidmodifying agents in ASDs.

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Many poorly water-soluble anticancer drugs also act as substrates for efflux transmembrane proteins, and this contributes to their poor oral bioavailability. For instance, docetaxel is a substrate for P-glycoprotein-mediated efflux pumps [254]. Song et al. developed partial ASDs of docetaxel with Lutrol® F68 (poloxamer 188) alone and with Pluronic® P85 (poloxamer 235) and Lutrol® F68 (poloxamer 188). They found that both solid dispersions enhanced the dissolution of docetaxel; however, the bioavailability enhancement in rats, from the former was 1.39-fold, while the latter enhanced bioavailability by 2.97-fold [255]. This was because Lutrol ® F68 along with Pluronic® P85 synergistically exhibited P-glycoprotein efflux pump inhibitory activity. Miao et al. developed an ASD of paclitaxel with HPMCAS and Poloxamer 188 [256]. This ASD enhanced the solubility and permeability of paclitaxel, thereby enhancing its bioavailability by 1.78-fold compared to physical mixtures [256]. HM30181A enables the oral dosing of paclitaxel (Oraxol™), irinotecan (Oratecan™), and docetaxel (Oradoxel™), by specifically inhibiting P-glycoprotein efflux pumps [257]. Shanmugam et al. developed an ASD of paclitaxel and administered it with HM30181A and saw a further bioavailability enhancement of 25% greater than Oraxol™ in dogs [258].

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Many poorly water-soluble anticancer drugs undergo significant first-pass metabolism by enzymes such as CYP3A. Thus, ASDs of anticancer drugs such as paclitaxel can be developed with—or administered with—CYP3A substrates such as cyclosporine A to enhance the drug’s apparent aqueous solubility and reduce first-pass metabolism [181]. Bohr et al. developed a co-amorphous formulation of docetaxel with bicalutamide at a 1:1 molar ratio [61]. This amorphous formulation can enhance the solubility of docetaxel and bicalutamide [61]. Moreover, bicalutamide was reported to inhibit efflux pumps as well as CYP enzymes, thereby enhancing the absorption of docetaxel. In a pharmacokinetic study in rats, this amorphous formulation showed a bioavailability enhancement of 15-fold for docetaxel and 3-fold for bicalutamide compared to their crystalline forms [61]. It is important to note that this amorphous formulation can have a risk of poor stability and can be further improved by formulating it as an ASD with the addition of polymers. Acetyl‐11‐ keto‐beta‐boswellic acid (AKBA) is a poorly water-soluble drug as well as a CYP3A4 substrate, and it has demonstrated promising antitumor effects [259, 260]. Miller et al. developed ASDs of AKBA and Ritonavir, a CYP3A4 inhibitor, thereby enhancing the dissolution , permeability, and thus the oral bioavailability of AKBA [259].

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Majority of research has been focused on the ability of ASDs to enhance the aqueous solubility of poorly water-soluble anticancer drugs and their permeability enhancement is achieved by a general approach of co-administering permeation enhancing drugs. However, the role of ASDs in enhancing the permeability of poorly water-soluble drugs is not limited to only the addition or coadministration of efflux pump inhibitors or enzyme inhibitors. In fact, ASDs can simultaneously enhance solubility and permeability by supersaturating the dissolved drug in the gastrointestinal tract, thereby saturating the efflux pumps or enzymes, hence enabling higher drug permeation. For example, Beig et al. developed an ASD of etoposide with PVPVA and Eudragit L-100. They demonstrated this ASD’s ability not only to enhance etoposide’s dissolution, but also to enhance its permeability in rats, to levels comparable with the potent P-glycoprotein inhibitor GF120918 [261]. Exemestane is anticancer drug used in the treatment of breast cancer. It exhibits poor water solubility and poor permeability [262]. Kaur et al. developed an ASD of exemestane with phospholipids, bile salts, and cyclodextrins. This ASD exhibited a 5.2-fold dissolution enhancement, a permeability enhancement of 4.6-fold across Caco-2 cell line, and a 2.3-fold increase in bioavailability in rats [262]. In this case, the amorphization of exemestane led to this apparent increase in water solubility, and bile salts formed mixed micelles with phospholipids, which increased the transcellular uptake of exemestane [262]. Other attempts to simultaneously enhance exemestane’s solubility and permeability through ASDs have been reported [263, 264].

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Thus, the rational design of ASDs of poorly water-soluble anticancer drugs can enhance the oral bioavailability of these drugs by increasing their apparent aqueous solubility, preventing polymorphic transitions, decreasing their degradation in gastric juices, decreasing their elimination by efflux proteins, and reducing their first-pass metabolism.

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6.2. Reducing Pharmacokinetic Variability: Pharmacokinetic variability describes the variations in a drug’s pharmacokinetic parameters. This variability results in fairly different plasma concentration–time profiles after the administration of the same dose to the same patient or different patients. Pharmacokinetic variability can be seen within the same patient (i.e., intrapatient or intrasubject pharmacokinetic variability) or it can be seen between different patients (i.e., interpatient or inter-subject pharmacokinetic variability). For the purpose of bioequivalence studies, the FDA defines a drug to be highly variable when its intrasubject pharmacokinetic variability is ≥ 30% [265]. Pharmacokinetic variability for anticancer drugs could occur due to changes in absorption, metabolism, distribution, or excretion [266]. In this review, we focus only on the pharmacokinetic variability that occurs due to changes during the absorption process. In fact, one of the main sources of intrasubject and intersubject pharmacokinetic variability for anticancer drugs is the process of drug absorption. The estimated intersubject variability in the absorption (estimated as the first-order rate constant, Ka) for anticancer drugs ranges from 40% to > 100% [152, 266, 267].

Journal Pre-proof Pharmacokinetic variability can have significant implications for anticancer drugs’ therapeutic outcomes. Several anticancer drugs have a narrow therapeutic window. Therefore, high pharmacokinetic variability can lead to plasma–drug concentrations above the minimum toxic concentrations, thereby leading to toxicity. Similarly, high pharmacokinetic variability can lead to insignificant drug exposures or plasma–drug concentrations below the minimum effective concentration, thereby leading to suboptimum therapy.

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The pharmacokinetic variability of poorly water-soluble anticancer drugs can be reduced by ASD formulation compared to conventional oral formulations such as physical mixtures of the drug and excipients (Figure. 5b). As discussed earlier, there is significant variation in the pH of the gastrointestinal tract, and this variation can be exacerbated due to several reasons, including differences in the disease state of patients (e.g., gastric ulcers), differences in patient age (e.g., age-related reduction in gastric secretions), prandial status, and the presence of any comedications [266]. This variation in pH can alter drugs’ solubility, leading to significant pharmacokinetic variability.

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Proxalutamide (GT0918) is a potent androgen receptor pathway inhibitor being developed for the treatment of prostate cancer [268]. It exhibits strong pH-dependent solubility, as can be seen in Figure 6a, and it has the potential to exhibit high pharmacokinetic variability [269]. Yang et al. screened several pH modifiers and designed an ASD of proxalutamide with polymer polyvinyl pyrrolidine and pH modifier citric acid. The rationale behind this design was that the pH modifier alters and maintains the microenvironmental pH around the proxalutamide dissolution boundary, thereby making its dissolution independent of changes in the pH of bulk dissolution media. Yang et al. carried out pharmacokinetic studies in dogs (Figure 6b) of the pH-modified ASD tablet versus the conventional tablet. They found that the co-efficient of variation (%CV) for the area under the plasma concentration–time curve (AUC0-∞) dropped from 52% to 21% [269].

Figure 6. (a) pH-solubility profile of GT0918 (proxalutamide) at 37 °C and (b) plasma concentration–time profiles of GT0918 (proxalutamide) in beagle dogs after a single-dose oral administration of pH-modified solid dispersion tablets (□) and conventional tablets (Δ). Reproduced with permission [269].

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Several anticancer drugs exhibit strong food effects on their pharmacokinetics, thereby leading to significant pharmacokinetic variability when prandial status and food content is not controlled. The rationale design of ASDs of such anticancer drugs can significantly lessen these food effects. For instance, if an anticancer drug shows significantly positive food effects with a high-fat diet, an ASD of such a drug with lipidic components and surfactants could eliminate the food effects and thus eliminate the variability. The food effects are eliminated because the lipids and surfactants help complete drug dissolution through emulsification, thereby eliminating the role of high-fat foods in the drug’s dissolution and absorption. Solyomosi et al. designed an amorphous system (presumably an ASD) of abiraterone acetate with Soluplus® and demonstrated an increase in the bioavailability of abiraterone, elimination of its positive food effects, and a reduction in its pharmacokinetic variability [270].

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Other factors that can contribute to the pharmacokinetic variability of anticancer drugs between patients, including differences in the expression of efflux transporter proteins such as Pglycoprotein efflux pumps, due to genetic polymorphism or differences in the expression of metabolizing enzymes such as dihydropyrimidine dehydrogenase, which is also due to polymorphism in the genes responsible for coding for the enzyme [91, 266]. ASDs developed with excipients or other drugs that act as substrates or inhibitors of such efflux pumps or enzymes can eliminate the pharmacokinetic variability that arises from different expressions of such proteins or enzymes.

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Moes et al. reported clinical testing of a docetaxel ASD, discussed above, along with administration of ritonavir, which is a CYP3A4 inhibitor [228]. Compared to a docetaxel premix solution, the docetaxel ASD showed a marked decrease in intersubject variability in cancer patients, with %CV reducing from 85% to 43% for AUC0-24 and 84% to 51% for Cmax [228]. Thus, the increase in the accuracy of dosing for docetaxel with reduced pharmacokinetic variability paved the way for its chronic use in metronomic dosing. Erlotinib shows a high intrapatient and interpatient pharmacokinetic variability due to its poor water solubility, its pre-systemic metabolism, its drug–drug interactions, and food effects [271]. Truong et al. developed an ASD of erlotinib with self-emulsifying components and demonstrated a reduction in the intersubject variability of AUC0-∞ by 86% and of Cmax by 70% in rats[271]. Hence, ASDs can reduce the pharmacokinetic variability of poorly water-soluble anticancer drugs by reducing pH and ionization state effects on solubility, eliminating food effects, reducing efflux, and eliminating pre-systemic metabolism. 6.3. Enhancing Pharmacokinetic Linearity: Drugs can exhibit linear or nonlinear pharmacokinetics. Linear pharmacokinetics implies that the area under the drug plasma concentration–time curve (AUC) is directly proportional to the dose [266, 272]. Therefore, when the dose is doubled, the AUC is expected to double. The linearity of a drug’s pharmacokinetics can be affected by absorption, distribution, metabolism, or elimination [272]. In this review, we will discuss the factors related only to the absorption process. Ideally,

Journal Pre-proof anticancer drugs should exhibit linear pharmacokinetics, so that it is easier for the oncologist to fine-tune the doses and control therapeutic outcomes without significant need for drug concentration monitoring. The pharmacokinetic linearity of poorly water-soluble anticancer drugs can be enhanced by ASD formulation compared to conventional oral formulations such as physical mixtures of a drug and excipients (Figure. 5c).

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The two main absorption-related factors that affect the pharmacokinetic linearity of poorly watersoluble anticancer drugs are the drug’s solubility and the saturation of drug transporters. For poorly water-soluble anticancer drugs, there is a limitation to its solubility in gastrointestinal media and thus its absorption. So, such drugs may show a linear increase in the area under the drug plasma concentration–time curve (AUC) with increase in the dose at lower levels, but the AUC will plateau at higher doses. Since ASDs typically exhibit high apparent aqueous solubility (i.e., high saturation solubility), their AUCs tend to be directly proportional to the drug dose, even at higher doses.

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Elacridar is a potent inhibitor of P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP). It has the potential to be used as an absorption enhancer with several anticancer drugs [273]. However, its potential application is severely limited by its poor water solubility, and it also exhibits significant nonlinear pharmacokinetics [274]. Sawicki et al. developed binary and ternary ASDs of elacridar hydrochloride with polymers such as PVP, PVPVA, and surfactants such as sodium dodecyl sulfate. All solid dispersions demonstrated improvement in the dissolution of elacridar compared to physical mixtures with polymers and excipients. However, the ASD of elacridar with PVP and sodium dodecyl sulfate exhibited complete dissolution and was found to be thermodynamically stable [275]. They further developed tablets for oral administration with the elacridar ASD. The pharmacokinetics of these tablets were tested in an exploratory clinical trial in healthy volunteers at doses of 25 mg, 250 mg and 1,000 mg. The maximum plasma concentration (Cmax) and the area under the drug plasma concentration–time curve (AUC) were found to increase linearly over the entire dose range (i.e., 25–1,000 mg) [274]. Thus, with application of ASDs, a linear and acceptable pharmacokinetic profile of elacridar was developed, thereby enabling its use in future clinical trials with anticancer drugs [274]. LY3009120 is a novel pan-RAF inhibitor being investigated in the treatment of cancer patients with the KRAS, NRAS, or BRAF mutations [276]. For exploratory studies, when LY3009120 was dosed as a conventional formulation to rats and dogs, it showed an oral bioavailability of < 4% and a lack of a dose–exposure relationship [276]. Thus, an ASD of LY3009120 was developed with PVP-VA and sodium lauryl sulfate (SLS) [276, 277]. This ASD enhanced bioavailability in dogs by an impressive 102-fold compared to conventional formulations [277]. Also, the ASD enabled pharmacokinetic linearity between dose and exposure at dose levels ranging from 10–100 mg/kg in rats [276]. When drug transporters are essential for drug absorption, and when the saturation of the former causes nonlinearity in the pharmacokinetics of a drug, these problems can be resolved with modification of the dosage forms or the dosage regimen. For instance, the ASD can be used as a

Journal Pre-proof drug product intermediate and a controlled-release dosage form can be designed to synchronize with the saturation kinetics of drug transporters. Also, dosage regimens such as twice a day (B.I.D) or three times a day (T.I.D) can be designed to avoid saturation of drug transporters. Thus, ASDs can enhance the pharmacokinetic linearity of poorly water-soluble anticancer drugs, thereby enabling a linear dose–exposure relationship.

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6.4. Enhancing Efficacy: From the above discussion, it is evident that ASDs can enhance oral bioavailability, reduce pharmacokinetic variability, and enhance the pharmacokinetic linearity of poorly water-soluble anticancer drugs. These pharmacokinetic factors have a profound effect on the pharmacodynamics of anticancer drugs. The efficacy or the effectiveness of several anticancer drugs have demonstrated strong dependence on anticancer drug dose intensity and systemic exposure [278, 279].

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For poorly water-soluble anticancer drugs that have a wide therapeutic window, their efficacy can be enhanced using an ASD formulation compared to conventional oral formulations when their efficacy is directly proportional to the maximum plasma drug concentration, the minimum plasma drug concentration at its steady state, the area under the plasma drug concentration–time curve, or the duration of drug exposure (see Figure. 5d). Even when the poorly water-soluble anticancer drugs have narrow therapeutic windows, the therapeutic outcomes of such drugs can be improved by ASDs, which demonstrate controlled pharmacokinetics when their efficacy is dependent on the parameters described above. There remains a lack of literature that demonstrates the effect of ASDs in improving the pharmacodynamic efficacy of poorly watersoluble anticancer drugs.

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For the anticancer drug abiraterone, which is used in the treatment of metastatic castrationresistant prostate cancer, it has been demonstrated that the prostate-specific antigen (PSA) decay rate is directly proportional to the minimum plasma drug concentration at its steady state (i.e., Cminss) [280]. The treatment effect of abiraterone has been demonstrated to have a strong association with PSA kinetics, which in turn have a strong association with overall survival in prostate cancer patients [281]. Thus, elevating the Cminss for abiraterone led to a profound improvement in the therapeutic efficacy of abiraterone. For the current treatment with a conventional abiraterone formulation (Zytiga®), the average Cminss after three months of treatment initiation was found to be just 12 ng/mL [282]. Thus, if a formulation with an ASD of abiraterone is developed, it can elevate the plasma trough concentration of abiraterone and thereby elevate Cminss. This can improve the therapeutic efficacy of abiraterone. Drug resistance in cancer treatment is another challenge that limits the efficacy of anticancer drugs [283]. Abiraterone exhibits its anticancer effect by the inhibition of the CYP17A1 enzyme. It was found that resistance to CYP17A1 inhibition can occur at standard doses—i.e., drug exposure of abiraterone after a certain period of treatment [159]. Li et al. demonstrated that this resistance

Journal Pre-proof can be reversed by increasing abiraterone exposure, thereby stimulating other modes of action for abiraterone [159]. Such an increase in drug exposure can be achieved by ASDs.

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Gefitinib is an epidermal growth factor receptor inhibitor that shows potential for the treatment of several types of cancers. However, its efficacy is limited due to its poor oral bioavailability [284]. Godugu et al. developed an ASD of gefitinib that showed a 9.14-fold bioavailability enhancement in rats compared to its crystalline form [284]. Further, they showed significant tumor volume reduction in A431 xenograft tumor models in mice, by the gefitinib ASD compared to crystalline gefitinib [284]. Additionally, it was shown that the gefitinib ASD was able to increase its pharmacodynamic effects by significantly decreasing tumor progression biomarkers compared to crystalline gefitinib and the control arm [284]. This is yet another way in which ASDs can enhance the efficacy of poorly water-soluble anticancer drugs.

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6.5. Reducing Toxicity: The pharmacokinetics of poorly water-soluble drugs also affect the occurrence of toxicities. This is especially critical for anticancer drugs that have a narrow therapeutic window, and when their toxicities are directly proportional to the maximum plasma–drug concentration or the plasma– drug concentration alone. A high pharmacokinetic variability for such drugs means that at some points in time, their plasma–drug concentration could exceed the limit of safe concentrations and lead to toxicity, which can sometimes be life threatening for anticancer drugs [285].

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The occurrence of toxicity for poorly water-soluble anticancer drugs can be reduced by using ASD formulations compared to conventional oral formulations, because the ASDs exert better control over the anticancer drug’s pharmacokinetics (Figure. 5e). For sorafenib, an orally administered kinase inhibitor, high interpatient variability seemed to correlate with the occurrence of toxicity or subtherapeutic outcomes [21]. The interpatient variability range for the current conventional formulation of sorafenib (Nexavar®) is between 36% and 91% [13, 286]. Truong et al. developed an ASD of sorafenib with the polymer Soluplus® and the surfactant sodium lauryl sulfate (SLS). They demonstrated improvement in sorafenib’s bioavailability [19]. The pharmacokinetic studies for this ASD were performed in murine models, without actual dosage forms; therefore, they could not assess the apparent pharmacokinetic variability of sorafenib. However, this ASD formulation has the potential of reducing the pharmacokinetic variability of sorafenib, thus reducing sorafenib-associated toxicity. Thalidomide, a well-known example of a drug with high toxicity, is used in the treatment of certain cancers. It exhibits poor water solubility and high pharmacokinetic variability [287]. Barea et al. attempted to develop a solid dispersion of thalidomide with reduced crystallinity, and they demonstrated enhanced apparent solubility of thalidomide [287]. Thus, further attempts in the development of ASDs of thalidomide can reduce its pharmacokinetic variability and thus its potential toxicity. The concept of sustained-release ASDs can be applied to toxicity associated with reduced high plasma–drug concentrations of poorly water-soluble anticancer drugs [288]. Nintedanib is a poorly water-soluble anticancer drug with a meagre oral bioavailability of 4.7% [289]. In order to decrease its side effects, prolong its drug release, and improve patient compliance, a sustained-release formulation with improved

Journal Pre-proof bioavailability of nintedanib is desirable [289]. Liu et al. developed an ASD of nintedanib with PVP K30 and soybean lecithin, then granulated it with HPMC for sustained release. The sustainedrelease ASD of nintedanib enhanced its bioavailability by 1.6-fold compared to its current commercial formulation in rats. In addition, this formulation had a minimal impact on Cmax [289]. This formulation would have the potential to reduce the side effects of nintedanib. Thus, the rational design of ASDs can reduce the toxicity associated with the oral administration of poorly water-soluble anticancer drugs. In addition to the pharmacokinetic and pharmacodynamic advantages mentioned above, ASD formulations of poorly water-soluble anticancer drugs have other advantages, such as reducing drug doses and patient pill burden, which ultimately improves patient compliance.

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7. Case Studies of Commercial Oncology Products Based on ASDs: Table 4 lists commercially available oncology products based on ASDs [13, 40, 126, 290-295]:

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7.1. Vemurafenib (Zelboraf®, Roche/Genentech): Vemurafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation [126]. Vemurafenib has poor water solubility (< 0.1 µg/mL) and a LogP of 3. During its initial Phase I studies, a conventional formulation with the crystalline form of vemurafenib was used. It underwent polymorphic transition, resulting in poor oral bioavailability of vemurafenib [39]. Moreover, for the Phase I trial of vemurafenib, a dose of 1,600 mg was administered, which correlates to 32 capsules of the conventional formulation [296]. Thus, efficient oral delivery of vemurafenib seemed unfeasible. However, promising results were obtained for vemurafenib. There was a statistically significant exposure–response relationship between progression-free survival and vemurafenib exposure (Cmin) (p < 0.0001) (see Figure 7a) [297]. Thus, in order to harness the therapeutic potential of vemurafenib, a more orally bioavailable formulation was required. Shah et al. developed an ASD of vemurafenib with hypromellose acetate succinate using a solventcontrolled coprecipitation process [39]. The ASD of vemurafenib mitigated the risk of crystallization and polymorphic transition by stabilizing amorphous vemurafenib in the polymer matrix. In dissolution studies, the ASD of vemurafenib achieved 30 times more solubility than crystalline vemurafenib. Further, in human bioavailability studies, the ASD formulation of vemurafenib demonstrated a four- to five-fold increase in exposure compared to the crystalline drug (see Figure 7b) [39]. The literature has reported the recent development of KinetiSol®, an ASD of vemurafenib formulated using a solvent-free process [298]. Ellenberger et al. reported greater oral bioavailability of vemurafenib in a murine model over the ASD developed by Shah et al. This indicates the potential for further enhancement of the oral delivery of vemurafenib. Additionally, the application of ASDs enabled a twice-daily dose of 960 mg of vemurafenib, which significantly reduced patient pill burden (i.e., four tablets twice daily) [296]. Ellenberger et al. demonstrated that the KinetiSol® processed ASD of vemurafenib also has potential for

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considerable reduction in patient pill burden [298]. Thus, the ASD technology effectively enabled the therapeutic application of vemurafenib.

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Figure 7. (a) Kaplan–Meier plots of overall survival data from trial 25026 showing a trend for exposure response. Low and high vemurafenib exposure were defined by patients with C min,tn values < or ≥ 39.0 μg/mL [Figure taken from [297]]. (b) Comparison of dose-normalized exposure data among three capsule formulations: Phase I crystalline vemurafenib and two ASD vemurafenib formulations (MBP) [Reproduced with permission [39]].

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7.2. Regorafenib (Stivarga®, Bayer): Regorafenib is a kinase inhibitor indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and—if the disease is the KRAS wild type—an anti-EGFR therapy [291]. Regorafenib is poorly water soluble (< 0.1 mg/mL) and has a LogP of 4.5. Due to its poor water solubility, an ASD of regorafenib with polyvinyl pyrrolidone (PVP K25) was developed. This enhanced the dissolution of regorafenib by 4.5 times compared to physical mixture of regorafenib with PVP [9, 13]. In pharmacokinetic studies, regorafenib ASD enhanced the bioavailability of regorafenib seven fold compared to its conventional formulation [9, 13]. Other attempts to develop ASDs of regorafenib have been reported [299]. 7.3. Everolimus (Afinitor®, Novartis): Everolimus is a kinase inhibitor indicated for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib [290]. Everolimus has poor oral bioavailability due its low water solubility, instability in the gastrointestinal tract, and intestinal efflux by p-glycoprotein transporters [300]. An ASD of everolimus with hydroxypropyl methylcellulose was developed using spray drying technology [40]. It demonstrated four times more dissolution than crystalline powder [13]. Other solid dispersions of everolimus have been reported, which exhibit even better dissolution than Afinitor® [300, 301].

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7.4. Venetoclax (Venclexta®, AbbVie): Venetoclax is a BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [292]. Venetoclax is poorly water soluble (< 0.01 mg/mL) and has a logP of 6.9. Due to its low water solubility, venetoclax has poor oral bioavailability. This necessitated a solubility-enhancing formulation to deliver an effective dose [302].

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In order to enhance the bioavailability of venetoclax, a lipid-based formulation and ASD formulations were developed. For ASD formulation venetoclax was first formulated with a polymer and surfactant. Thus two ASD formulations of venetoclax were made with polymer vinylpyrrolidone-vinyl acetate (Kollidon® VA 64) and surfactant polyoxyethylene sorbitan monooleate (Tween 80) in one formulation and the other formulation contained Kollidon® VA 64 with surfactant D -α-Tocopherol polyethylene glycol 1000 succinate (Vitamin E TPGS) at same level. It was seen that the Tween 80 based ASD could achieve a higher drug loading than Vitamin E TPGS based ASD [302]. Drug loading in ASD formulation is a critical parameter since it ultimately affects the pill burden. Thus, final ASD formulation of venetoclax with Kollidon® VA 64, Tween 80, and silica (Aerosil) was developed. In a pharmacokinetic study in dogs, the performance of this ASD surpassed that of a lipid formulation by 61% in drug exposure and hence was selected for further development [302]. Thus, the application of ASD technology enabled the delivery of effective doses of venetoclax.

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7.5. Olaparib (Lynparza®, AstraZeneca): Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. This drug is also indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy [303]. Olaparib has poor water solubility and a LogP of 2.7. In order to improve its bioavailability, olaparib was initially developed and commercialized as a capsule formulation containing crystalline olaparib and lauroyl macrogol glycerides [295]. In order to deliver a dose of 400 mg twice daily, a total of 16 capsules were required. This negatively affected patient compliance [294, 295]. In order to reduce the dose and the pill burden, a more bioavailable and robust formulation was desirable. Thus, an ASD of olaparib with vinylpyrrolidone-vinyl acetate formulated using melt extrusion was developed [294, 295]. Compared to its capsule formulation, the ASD enhanced bioavailability by 2.65 fold. Thus, the dose could be reduced to 300 mg twice a day. The application of ASD formulations enabled the development of a tablet with 150 mg olaparib. Hence, the pill burden was dramatically reduced from 16 capsules a day to four tablets a day [295]. Moreover, the olaparib ASD eliminated the food effect on drug absorption, as seen for the capsule formulation [295, 304]. The application of ASD formulations

Journal Pre-proof led to the development of a better product for olaparib, which improved patient compliance and hence improved therapeutic outcomes. Conclusion: Oral administration is the most preferred route for anticancer drug delivery. However, its application is limited owing to challenges associated with anticancer drugs’ physicochemical properties, predominantly poor water solubility, and the physiology of the gastrointestinal tract. ASD is a promising formulation development technology that can enhance the apparent aqueous solubility of poorly water-soluble anticancer drugs. ASD-based formulations can be adopted not only to improve the oral bioavailability of poorly water-soluble drugs but also to improve their pharmacokinetics and thus their efficacy and safety.

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The early adoption of ASD technology would enable faster development of dose-linear exposure over a wide range of doses, thereby enabling faster identification of NOAELs (no observed adverse effect levels) preclinically and MTDs (maximum tolerated doses) clinically. This would avoid the issue of reaching an exposure plateau using a conventional formulation, and it would eliminate the need for reformulation to characterize the anticancer drug candidate’s effective and toxic dose.

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Also, ASD technology would enable more consistent pharmacokinetics by reducing variability; therefore, statistically significant clinical signals could be achieved using fewer subjects and shorter trials. Early implementation of ASD technology in the oncology product development process could make lifesaving anticancer drugs available to patients more quickly. Additionally, early implementation of ASD technology could help mitigate the risk of false termination of lifesaving anticancer drug candidates due to safety or efficacy issues that could simply be the result of erratic pharmacokinetics or poor bioavailability. The success of commercial ASD-based oncology products demonstrates that adopting ASD formulation technology leads to improved therapeutic outcomes in the field of oncology. Table 1. Benefits of administering anticancer drugs orally. Benefits References Personnel Benefits Patient Perspective   

Oncologist Perspective

Independence, homebased therapy Scheduling ease



Patient compliance

[15, 78-80]



Better tolerability

[14, 15]

No needles, pain-free administration, reduced risk of infections



Ease of dosing, staff savings

[81, 82]

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

In several surveys, cancer patients clearly preferred oral chemotherapy over intravenous chemotherapy (e.g., > 89%)

One survey found that more than 80% of oncologists in the US had increased their prescription of oral anticancer drugs over the period of analysis (two years).

Pharmacoeconomic Benefits

[15, 78, 84-87]

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Comparatively cheaper medication

[82]



Reduced visits



Resources savings

[15] [15, 88]

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

Hospitalization Costs

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Medication Costs

[15, 16, 83]

Ease of withdrawal, in the event of toxicity Ease of dose modification

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



No hospitalization needed, reduced travel time and cost Minimal monitoring/ laboratory testing

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

An Italian analysis demonstrated that oral capecitabine was the “dominant strategy” in pharmacoeconomic terms, providing a savings from the Italian hospital perspective of €2,234 per patient compared to intravenous treatment with fluorouracil/leucovorin.

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One study found that oral chemotherapy was associated with a 36% reduction in cost for breast cancer patients and a 43% reduction in cost for colon cancer patients compared to intravenous chemotherapy.

Staff savings- [15] oncologist, nurses time and availability

na



Pharmacological Benefits Continuous/Chronic Therapy

Co-Therapy

[89, 90]

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

Makes metronomic (low-dose continuous) dosing feasible

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[14, 91]

Reduces the severity of toxicity associated with combination or co-therapy with oral chemotherapy compared to intravenous chemotherapy

[92, 93]

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[94]

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One example is the continuous administration of tyrosine kinase inhibitors for better therapeutic outcomes.

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Table 2. List of poorly water-soluble anticancer drugs that are substrates for major efflux pumps located on the intestinal membrane. [167, 172-174]: Efflux Pump Substrates

na

mitomycin c, vinblastine, vincristine, vinorebline, vindesine, etoposide, paclitaxel, doxorubicin, daunorubicin, epirubicin, idarubicin, docetaxel, imatinib, irinotecan, SN-38

ur

(7-ethyl-10-hydroxycampothecin), topotecan tamoxifen, methotrexate, mitoxantrone, amsacrine,

P-gp, ABCB1

5-fluorouracil,

actinomycin

d, bisantrene,

chlorambucil, cisplatin,

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cytarabine, gefitinib, teniposide, afatinib, alectinib (m-4), axitinib, bosutinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, erlotinib, lapatinib, lenvatinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, sorafenib, sunitinib, trametinib, vemurafenib doxorubicin, daunorubicin, epirubicin, idarubicinol, mitoxantrone, irinotecan, SN-38 (7-

BCRP ABCG2

,

ethyl-10-hydroxycampothecin),

imatinib,

methotrexate,

topotecan,

bisantrene,

teniposide, topotecan, afatinib, axitinib, dabrafenib, dasatinib, erlotinib, gefitinib, lapatinib, lenvatinib, nilotinib, osimertinib, pazopanib, ponatinib, regorafenib, vemurafenib

MRP2

, cabozantinib, sorafenib, cisplatin, vincristine, vinblastine, etoposide, doxorubicin,

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daunorubicin,

epirubicin,

irinotecan,

SN-38

(7-ethyl-10-hydroxycampothecin),

methotrexate, mitoxantrone, mitomycin c, 5-fluorouracil

Cabozantinib

Fed: High-fat meal

Erlotinib

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Dabrafenib

Fed: Low-fat meal

Fed: High-fat meal

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Ceritinib

na

Fed: High-fat meal

Fed

Fed: Low-fat meal

Lapatinib Fed: High-fat meal Fed: High-fat meal Midostaurin

Neratinib Nilotinib

Fed: Standard meal Fed: High-fat meal Fed: High-fat meal

Cmax↑ 1.8-fold AUC0-∞↑ 1.7-fold

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Fed: High-fat meal

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Bosutinib monohydrate

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Table 3. List of poorly water-soluble anticancer drugs demonstrating prominent food effects on their pharmacokinetics. Pharmacokinetic Implication Anticancer Drug Prandial State References (compared to fasted state) Cmax↑ 7-fold Fed: Low-fat meal AUC0-∞↑ 5-fold Abiraterone [201] acetate Cmax↑ 17-fold Fed: High-fat meal AUC0-∞↑ 10-fold Axitinib (Polymorph Cmax↓ 38% Fed form IV) AUC0-∞↓ 23% [202] Axitinib (Polymorph No clinically significant Fed: High and Moderate fat form XLI) pharmacokinetic implication.

Cmax↑ 40.5% AUC0-∞↑ 57% Cmax↑ 41% AUC0-∞↑ 73% Cmax↑ 43% AUC0-∞↑ 58% Cmax↓ 51% AUC0-∞↓ 31% Cmax↑ 36% AUC0-24↑ 54% Cmax↑ 2.42-fold AUC0-∞↑ 2.67-fold Cmax↑ 3.03-fold AUC0-∞↑ 4.25-fold Cmax↓ 27% AUC0-∞↑ 59% Cmax↓ 20% AUC0-∞↑ 22% Cmax↑ 1.7-fold AUC0-∞↑ 2.2-fold Cmax↑ 112%

[203] [204]

[205]

[206] [207]

[208]

[209]

[210] [211]

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Anticancer Drug

Nintedanib

Pharmacokinetic Implication (compared to fasted state) AUC0-∞↑ 82% Cmax↑ 20% AUC0-∞↑ 20% Cmax↑ 2.10-fold AUC0-72↑ 1.92-fold Cmax↑ 2.08-fold AUC0-72↑ 2.34-fold Cmax↑ 7.78-fold AUC0-∞↑ 7.38-fold Cmax↓ 68% AUC0-∞↓ 15%

Prandial State

Fed Fed: Low-fat meal

Sonidegib

Fed: High-fat meal Fed

[212]

[213]

[214] [215]

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Fed: High-fat meal

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Pazopanib

References

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Table 4. Commercial Oncology Products Based on Amorphous Solid Dispersions. anticancer Structure Water Drug Product drug Solubility

Stivarga®, Bayer

polyvinyl pyrrolidone

0.00163 mg/mL

Afinitor®, Novartis

hydroxypropyl methylcellulose

Venetoclax

0.000933 mg/mL

Venclexta®, AbbVie

Olaparib

0.119 mg/mL

Lynparza®, AstraZeneca

vinylpyrrolidonevinyl acetate, polyoxyethylene sorbitan monooleate, silica vinylpyrrolidonevinyl acetate

Everolimus

ur

0.00102 mg/mL

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Regorafenib

0.000362 mg/mL

na

Vemurafenib

Excipients used in amorphous solid dispersion Zelboraf®,Roche/Genentech hypromellose acetate succinate

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References 1. Torre, L.A., et al., Global cancer statistics, 2012. CA: A Cancer Journal for Clinicians, 2015. 65(2): p. 87-108. 2. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2019. 2019. 69(1): p. 7-34. 3. Haberman, A. MIT study finds that the probability of clinical trial success is nearly 40% higher than previously thought. 2018 4/10/2019]; Available from: https://biopharmconsortium.com/2018/03/14/mit-study-finds-that-the-probability-of-clinicaltrial-success-is-nearly-40-higher-than-previously-thought/. 4. Zamboni, W.C., et al., Best practices in cancer nanotechnology: perspective from NCI nanotechnology alliance. Clin Cancer Res, 2012. 18(12): p. 3229-41. 5. Wong, C.H., K.W. Siah, and A.W. Lo, Estimation of clinical trial success rates and related parameters. Biostatistics, 2018. 20(2): p. 273-286. 6. Hoelder, S., P.A. Clarke, and P. Workman, Discovery of small molecule cancer drugs: Successes, challenges and opportunities. Molecular Oncology, 2012. 6(2): p. 155-176. 7. Di, L., P.V. Fish, and T. Mano, Bridging solubility between drug discovery and development. Drug Discovery Today, 2012. 17(9): p. 486-495. 8. Adams, D.J., The Valley of Death in anticancer drug development: a reassessment. Trends in pharmacological sciences, 2012. 33(4): p. 173-180. 9. Tran, P., et al., Overview of the Manufacturing Methods of Solid Dispersion Technology for Improving the Solubility of Poorly Water-Soluble Drugs and Application to Anticancer Drugs. Pharmaceutics, 2019. 11(3): p. 132. 10. Gupta, S.C., et al., Cancer drug discovery by repurposing: teaching new tricks to old dogs. Trends Pharmacol Sci, 2013. 34(9): p. 508-17. 11. Benjamin, D., et al., Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov, 2011. 10(11): p. 868-80. 12. Xie, J., X. Wang, and C.G. Proud, mTOR inhibitors in cancer therapy. F1000Research, 2016. 5: p. F1000 Faculty Rev-2078. 13. Sawicki, E., et al., Inventory of oral anticancer agents: pharmaceutical formulation aspects with focus on the solid dispersion technique. Cancer Treatment Reviews, 2016. 50: p. 247-263. 14. Mazzaferro, S., K. Bouchemal, and G. Ponchel, Oral delivery of anticancer drugs I: general considerations. Drug Discov Today, 2013. 18(1-2): p. 25-34. 15. Banna, G.L., et al., Anticancer oral therapy: emerging related issues. Cancer Treat Rev, 2010. 36(8): p. 595-605. 16. Batlle, J.F., et al., Oral chemotherapy: potential benefits and limitations. J Revista de Oncología, 2004. 6(6): p. 335-340. 17. Ben Mousa, A., Sorafenib in the treatment of advanced hepatocellular carcinoma. Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association, 2008. 14(1): p. 40-42. 18. Gong, L., et al., PharmGKB summary: sorafenib pathways. Pharmacogenetics and genomics, 2017. 27(6): p. 240-246. 19. Truong, D.H., et al., Preparation and characterization of solid dispersion using a novel amphiphilic copolymer to enhance dissolution and oral bioavailability of sorafenib. Powder Technology, 2015. 283: p. 260-265. 20. Boudou-Rouquette, P., et al., Early Sorafenib-Induced Toxicity Is Associated with Drug Exposure and UGTIA9 Genetic Polymorphism in Patients with Solid Tumors: A Preliminary Study. PLOS ONE, 2012. 7(8): p. e42875.

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31. 32. 33. 34. 35.

36. 37. 38. 39.

40.

41. 42.

43.

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29.

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27. 28.

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25. 26.

na

23. 24.

ur

22.

Boudou-Rouquette, P., et al., Variability of sorafenib toxicity and exposure over time: a pharmacokinetic/pharmacodynamic analysis. 2012. 17(9): p. 1204-1212. Straubinger, R.M., Biopharmaceutics of paclitaxel (Taxol): formulation, activity, and pharmacokinetics. 1995: p. 237-258. Gelderblom, H., et al., Cremophor EL. European Journal of Cancer, 2001. 37(13): p. 1590-1598. Rowinsky, E.K., et al., Clinical toxicities encountered with paclitaxel (Taxol). Semin Oncol, 1993. 20(4 Suppl 3): p. 1-15. Weiss, R.B., et al., Hypersensitivity reactions from taxol. J Clin Oncol, 1990. 8(7): p. 1263-8. Arpicco, S., et al., Anticancer prodrugs: an overview of major strategies and recent developments. Curr Top Med Chem, 2011. 11(18): p. 2346-81. Chadha, R., et al., Drug carrier systems for anticancer agents: A review. 2008. Lvov, Y.M., et al., Converting Poorly Soluble Materials into Stable Aqueous Nanocolloids. Langmuir, 2011. 27(3): p. 1212-1217. Mazzaferro, S., K. Bouchemal, and G. Ponchel, Oral delivery of anticancer drugs III: formulation using drug delivery systems. Drug Discov Today, 2013. 18(1-2): p. 99-104. Mazzaferro, S., K. Bouchemal, and G. Ponchel, Oral delivery of anticancer drugs II: the prodrug strategy. Drug Discovery Today, 2013. 18(1): p. 93-98. Narvekar, M., et al., Nanocarrier for poorly water-soluble anticancer drugs--barriers of translation and solutions. AAPS PharmSciTech, 2014. 15(4): p. 822-33. Shin, H.-C., et al., Multi-drug loaded polymeric micelles for simultaneous delivery of poorly soluble anticancer drugs. Journal of Controlled Release, 2009. 140(3): p. 294-300. Sun, L., et al., Functional nanoemulsion-hybrid lipid nanocarriers enhance the bioavailability and anti-cancer activity of lipophilic diferuloylmethane. Nanotechnology, 2016. 27(8): p. 085102. Xie, Y., et al., Carrier-Free Microspheres of an Anti-Cancer Drug Synthesized via a Sodium Catalyst for Controlled-Release Drug Delivery. Materials, 2018. 11(2): p. 281. Crist, R.M., et al., Common Pitfalls in Nanotechnology: Lessons Learned from NCI’s Nanotechnology Characterization Laboratory. Integrative biology : quantitative biosciences from nano to macro, 2013. 5(1): p. 10.1039/c2ib20117h. Lee, J.J., L. Saiful Yazan, and C.A. Che Abdullah, A review on current nanomaterials and their drug conjugate for targeted breast cancer treatment. Int J Nanomedicine, 2017. 12: p. 2373-2384. Shah, N., et al., Amorphous Solid Dispersions : Theory and Practice. 2014 ed. 2014, New York, NY: Springer. Van den Mooter, G., The use of amorphous solid dispersions: A formulation strategy to overcome poor solubility and dissolution rate. Drug Discovery Today: Technologies, 2012. 9(2): p. e79-e85. Shah, N., et al., Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer‐stabilized solid dispersion prepared by a solvent‐controlled coprecipitation process. Journal of pharmaceutical sciences, 2013. 102(3): p. 967-981. Jermain, S.V., C. Brough, and R.O. Williams, Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery – An update. International Journal of Pharmaceutics, 2018. 535(1): p. 379-392. Gallo, J.M., Pharmacokinetic/Pharmacodynamic-Driven Drug Development. The Mount Sinai journal of medicine, New York, 2010. 77(4): p. 381-388. Wong, C.C., K.-W. Cheng, and B. Rigas, Preclinical predictors of anticancer drug efficacy: critical assessment with emphasis on whether nanomolar potency should be required of candidate agents. The Journal of pharmacology and experimental therapeutics, 2012. 341(3): p. 572-578. Cragg, G.M., D.J. Newman, and D.G.I. Kingston, 2.02 - Terrestrial Plants as a Source of Novel Pharmaceutical Agents, in Comprehensive Natural Products II, H.-W. Liu and L. Mander, Editors. 2010, Elsevier: Oxford. p. 5-39.

Jo

21.

Journal Pre-proof

51. 52. 53. 54.

55.

56.

57. 58. 59.

60.

61.

of

ro

50.

-p

49.

re

48.

lP

47.

na

46.

ur

45.

Hearn, B.R., S.J. Shaw, and D.C. Myles, 7.04 - Microtubule Targeting Agents, in Comprehensive Medicinal Chemistry II, J.B. Taylor and D.J. Triggle, Editors. 2007, Elsevier: Oxford. p. 81-110. Turkson, J., Cancer drug discovery and anticancer drug development, in The Molecular Basis of Human Cancer. 2017, Springer. p. 695-707. Curatolo, W., Physical chemical properties of oral drug candidates in the discovery and exploratory development settings. Pharmaceutical Science & Technology Today, 1998. 1(9): p. 387-393. Chessum, N., et al., Chapter One - Recent Advances in Cancer Therapeutics, in Progress in Medicinal Chemistry, G. Lawton and D.R. Witty, Editors. 2015, Elsevier. p. 1-63. Wang, A.Z., Giving failed drugs a fresh chance: a new direction for nanoparticle drug delivery. Expert Review of Medical Devices, 2012. 9(5): p. 445-447. Graves, R.A., et al., Formulation and evaluation of biodegradable nanoparticles for the oral delivery of fenretinide. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2015. 76: p. 1-9. Obata, T., et al., Improvement of the Antitumor Activity of Poorly Soluble Sapacitabine (CS-682) by Using Soluplus® as a Surfactant. Biological and Pharmaceutical Bulletin, 2014. 37(5): p. 802807. Lipinski, C.A., Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods, 2000. 44(1): p. 235-49. Veber, D.F., et al., Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem, 2002. 45(12): p. 2615-23. DeGoey, D.A., et al., Beyond the Rule of 5: Lessons Learned from AbbVie’s Drugs and Compound Collection. Journal of Medicinal Chemistry, 2018. 61(7): p. 2636-2651. Lipinski, C.A., et al., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev, 2001. 46(1-3): p. 3-26. Lukyanov, A.N. and V.P. Torchilin, Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs. Advanced Drug Delivery Reviews, 2004. 56(9): p. 12731289. Surapaneni, M.S., S.K. Das, and N.G. Das, Designing Paclitaxel drug delivery systems aimed at improved patient outcomes: current status and challenges. ISRN pharmacology, 2012. 2012: p. 623139-15. Kingston, D.G.I., The shape of things to come: Structural and synthetic studies of taxol and related compounds. Phytochemistry, 2007. 68(14): p. 1844-1854. Kingston, D.G.I. and J.P. Snyder, The Quest for a Simple Bioactive Analog of Paclitaxel as a Potential Anticancer Agent. Accounts of Chemical Research, 2014. 47(8): p. 2682-2691. Baghel, S., H. Cathcart, and N.J. O'Reilly, Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs. Journal of Pharmaceutical Sciences, 2016. 105(9): p. 2527-2544. Szczurek, J., et al., Molecular Dynamics, Recrystallization Behavior, and Water Solubility of the Amorphous Anticancer Agent Bicalutamide and Its Polyvinylpyrrolidone Mixtures. Molecular pharmaceutics, 2017. 14(4): p. 1071-1081. Bohr, A., et al., Efflux Inhibitor Bicalutamide Increases Oral Bioavailability of the Poorly Soluble Efflux Substrate Docetaxel in Co-Amorphous Anti-Cancer Combination Therapy. Molecules (Basel, Switzerland), 2019. 24(2): p. 266.

Jo

44.

Journal Pre-proof

69.

70. 71. 72. 73.

74.

75. 76.

77.

78. 79.

80. 81.

of

ro

68.

-p

67.

re

66.

lP

65.

na

64.

ur

63.

Dokoumetzidis, A. and P. Macheras, A century of dissolution research: From Noyes and Whitney to the Biopharmaceutics Classification System. International Journal of Pharmaceutics, 2006. 321(1): p. 1-11. Leuner, C. and J. Dressman, Improving drug solubility for oral delivery using solid dispersions. European Journal of Pharmaceutics and Biopharmaceutics, 2000. 50(1): p. 47-60. Leleux, J. and R.O. Williams, Recent advancements in mechanical reduction methods: particulate systems. Drug Development and Industrial Pharmacy, 2014. 40(3): p. 289-300. Chiou, W.L. and S. Riegelman, Pharmaceutical Applications of Solid Dispersion Systems. Journal of Pharmaceutical Sciences, 1971. 60(9): p. 1281-1302. Sun, Y., et al., Stability of Amorphous Pharmaceutical Solids: Crystal Growth Mechanisms and Effect of Polymer Additives. The AAPS Journal, 2012. 14(3): p. 380-388. Nurzyńska, K., et al., Long-Term Amorphous Drug Stability Predictions Using Easily Calculated, Predicted, and Measured Parameters. Molecular Pharmaceutics, 2015. 12(9): p. 3389-3398. Meng, F., U. Gala, and H. Chauhan, Classification of solid dispersions: correlation to (i) stability and solubility (ii) preparation and characterization techniques. Drug Development and Industrial Pharmacy, 2015. 41(9): p. 1401-1415. Sarode, A.L., et al., Hot melt extrusion (HME) for amorphous solid dispersions: Predictive tools for processing and impact of drug–polymer interactions on supersaturation. European Journal of Pharmaceutical Sciences, 2013. 48(3): p. 371-384. Singh, A. and G. Van den Mooter, Spray drying formulation of amorphous solid dispersions. Advanced Drug Delivery Reviews, 2016. 100: p. 27-50. Zhang, M., et al., Formulation and delivery of improved amorphous fenofibrate solid dispersions prepared by thin film freezing. Eur J Pharm Biopharm, 2012. 82(3): p. 534-44. Nagy, Z.K., et al., High speed electrospinning for scaled-up production of amorphous solid dispersion of itraconazole. International Journal of Pharmaceutics, 2015. 480(1): p. 137-142. Kulthe, V.V., P.D. Chaudhari, and H.Y. Aboul-Enein, Freeze-dried amorphous dispersions for solubility enhancement of thermosensitive API having low molecular lipophilicity. Drug Res (Stuttg), 2014. 64(9): p. 493-8. Ellenberger, D.J., D.A. Miller, and R.O. Williams Iii, Expanding the Application and Formulation Space of Amorphous Solid Dispersions with KinetiSol®: a Review. AAPS PharmSciTech, 2018. 19(5): p. 1933-1956. LaFountaine, J.S., J.W. McGinity, and R.O. Williams, Challenges and Strategies in Thermal Processing of Amorphous Solid Dispersions: A Review. AAPS PharmSciTech, 2016. 17(1): p. 43-55. Miller, D.A., James C. DiNunzio, Justin R. Hughey, Robert O. Williams III, and James W. McGinity., KinetiSol®: A New Processing Paradigm for Amorphous Solid Dispersion Systems. Drug Development & Delivery, 2012. 12(9). Miller, D.A.a.J.M.K., KinetiSol®-Based Amorphous Solid Dispersions, in Amorphous Solid Dispersions- Theory and Practice, N. Shah, Sandhu, H., Choi, D.S., Chokshi, H., Malick, A.W. , Editor. 2014, Springer-Verlag New York. Paley, M., et al., Preferences for oral and parenteral antitumor therapy: A survey of 260 patients with metastatic breast cancer. 2005. 23(16_suppl): p. 619-619. Catania, C., et al., Perception that oral anticancer treatments are less efficacious: development of a questionnaire to assess the possible prejudices of patients with cancer. Breast Cancer Res Treat, 2005. 92(3): p. 265-72. O'Neill, V.J. and C.J. Twelves, Oral cancer treatment: developments in chemotherapy and beyond. British Journal of Cancer, 2002. 87(9): p. 933-937. Borner, M., et al., Answering patients' needs: oral alternatives to intravenous therapy. Oncologist, 2001. 6 Suppl 4: p. 12-6.

Jo

62.

Journal Pre-proof

90. 91. 92.

93.

94. 95.

96.

97.

98. 99.

100.

of

89.

ro

88.

-p

87.

re

86.

lP

85.

na

84.

ur

83.

Findlay, M., G. von Minckwitz, and A. Wardley, Effective oral chemotherapy for breast cancer: pillars of strength. Ann Oncol, 2008. 19(2): p. 212-22. Terwogt, J.M.M., et al., Clinical pharmacology of anticancer agents in relation to formulations and administration routes. Cancer Treatment Reviews, 1999. 25(2): p. 83-102. Liu, G., et al., Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol, 1997. 15(1): p. 110-5. Wojtacki, J., et al., Breast cancer patients preferences for oral versus intravenous second-line anticancer therapy. EJC Supplements, 2006. 4(2): p. 159-160. Aisner, J., Overview of the changing paradigm in cancer treatment: Oral chemotherapy. American Journal of Health-System Pharmacy, 2007. 64(9 Supplement 5): p. S4-S7. Schott, S., et al., Acceptance of oral chemotherapy in breast cancer patients - a survey study. BMC cancer, 2011. 11(1): p. 129-129. Khandelwal, N., et al., Impact of Clinical Oral Chemotherapy Program on Wastage and Hospitalizations. 2011. 7(3S): p. e25s-e29s. Costanzo, F.D., et al., Capecitabine (X) vs. bolus 5-FU/LV as adjuvant chemotherapy for patients (pts) with Dukes’ C colon cancer: economic evaluation in an Italian hospital setting. 2006. 24(18_suppl): p. 13518-13518. Noxon, V. and J. Wu, The Costs Of Oral Versus Intravenous Chemotherapy In Insured, Low Income Patients With Breast Or Colon Cancer. Value in Health, 2013. 16(3): p. A133. Stuurman, F.E., et al., Oral anticancer drugs: mechanisms of low bioavailability and strategies for improvement. Clin Pharmacokinet, 2013. 52(6): p. 399-414. Moes, J., et al., Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel. European Journal of Pharmaceutics and Biopharmaceutics, 2013. 83(1): p. 87-94. Colleoni, M., et al., Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol, 2002. 13(1): p. 73-80. Herbrink, M., et al., Variability in bioavailability of small molecular tyrosine kinase inhibitors. Cancer Treat Rev, 2015. 41(5): p. 412-22. FDA. Hematology/Oncology (Cancer) Approvals & Safety Notifications. Hematology/Oncology (Cancer) Approvals & Safety Notifications 2000-2018 09/08/2018; Available from: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. FDA. Drugs@FDA: FDA Approved Drug Products. Drugs@FDA: FDA Approved Drug Products 2000-2018 09/08/2018]; Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Katz, A. Novel Oral Paclitaxel Formulation Aims to Overcome Drawbacks of IV Version. Oncolive 2018 [cited 2019 4/19/2019]; Available from: https://www.onclive.com/publications/oncologylive/2018/vol-19-no-21/novel-oral-paclitaxel-formulation-aims-to-overcome-drawbacks-of-ivversion. Lin, L. and H. Wong, Predicting Oral Drug Absorption: Mini Review on Physiologically-Based Pharmacokinetic Models. Pharmaceutics, 2017. 9(4): p. 41. Shah, V.P. and G.L. Amidon, G.L. Amidon, H. Lennernas, V.P. Shah, and J.R. Crison. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability, Pharm Res 12, 413–420, 1995—Backstory of BCS. The AAPS Journal, 2014. 16(5): p. 894-898. Gao, Y., C. Gesenberg, and W. Zheng, Chapter 17 - Oral Formulations for Preclinical Studies: Principle, Design, and Development Considerations, in Developing Solid Oral Dosage Forms (Second Edition), Y. Qiu, et al., Editors. 2017, Academic Press: Boston. p. 455-495.

Jo

82.

Journal Pre-proof

110. 111.

112. 113. 114. 115. 116.

117. 118.

119. 120.

of

109.

ro

107. 108.

-p

106.

re

105.

lP

104.

na

103.

ur

102.

Byrn, S.R., Zografi, G. and Chen, X., Polymorphs, in Solid State Properties of Pharmaceutical Materials. 2017. Byrn, S.R., Zografi, G. and Chen, X., Solvates and Hydrates, in Solid State Properties of Pharmaceutical Materials. 2017. Singhal, D. and W. Curatolo, Drug polymorphism and dosage form design: a practical perspective. Advanced Drug Delivery Reviews, 2004. 56(3): p. 335-347. Bellesoeur, A., et al., Axitinib in the treatment of renal cell carcinoma: design, development, and place in therapy. Drug Design, Development and Therapy, 2017. 11: p. 2801-2811. Censi, R. and P. Di Martino, Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs. Molecules, 2015. 20(10): p. 18759-76. Roy, S., R. Quiñones, and A.J. Matzger, Structural and Physicochemical Aspects of Dasatinib Hydrate and Anhydrate Phases. Crystal Growth & Design, 2012. 12(4): p. 2122-2126. Gabriel, O.S.F.M.J.G.A.V.K.F., Polymorphs of dasatinib and process for preparation thereof. 2010. Perlovich, G.L., et al., Polymorphism and solvatomorphism of bicalutamide. 2013. 111(1): p. 655662. Vega, D.R., et al., Conformational polymorphism in bicalutamide. Int J Pharm, 2007. 328(2): p. 112-8. Német, Z., J. Sztatisz, and Á. Demeter, Polymorph transitions of bicalutamide: A remarkable example of mechanical activation. 2008. 97(8): p. 3222-3232. Kersten, K.M. and A.J. Matzger, Improved pharmacokinetics of mercaptopurine afforded by a thermally robust hemihydrate. Chemical communications (Cambridge, England), 2016. 52(30): p. 5281-5284. Raza, K., et al., Polymorphism: The Phenomenon Affecting the Performance of Drugs. Vol. 1. 2014. 10. Yokoyama, T., et al., Studie on drug nonequivalence. X. Bioavailability of 6-mercaptopurine polymorphs. Chem Pharm Bull (Tokyo), 1981. 29(1): p. 194-9. EMA, Nexavar - Sorafenib - Scientific Discussion. 2006. Ales Gavenda, O.-L.C., et al., Polymorphs of sorafenib tosylate and sorafenib hemi-tosylate, and processes for preparation thereof. 2009. Jiang, S., et al., Solubility Correlation and Thermodynamic Analysis of Sorafenib Free Base and Sorafenib Tosylate in Monosolvents and Binary Solvent Mixtures. Journal of Chemical & Engineering Data, 2017. 62(1): p. 259-267. Tesson, N., et al., Scalable process for the preparation of sorafenib tosylate ethanol solvate and sorafenib tosylate form iii. 2015. Lindemann, C., D. Watson, and D. Corson, Solid-State Characterization of Seven Isomorphic Solvates of ARRY-380. 2012, Array Biopharma: American Association of Pharmaceutical Scientists, Annual Meeting and Exposition. Corson, D., C. Lindemann, and D.J. Watson, Polymorphs of arry-380, a selective herb2 inhibitor and pharmaceutical compositions contianing them. 2012. C. Lindemann, et al., Amorphous Dispersion Development of ARRY-380, an ErbB2

Jo

101.

Selective Inhibitor. 2012, Array Biopharma: American Association of Pharmaceutical Scientists, Annual Meeting and Exposition. 121. Chennuru, R., et al., In Situ Metastable Form: A Route for the Generation of Hydrate and Anhydrous Forms of Ceritinib. Crystal Growth & Design, 2017. 17(12): p. 6341-6352. 122. Lili Feng, P.B., NJ (US); Baoqing Gong, Morris Plains, NJ (US);, et al., Crystalline Forms Of 5Chloro-N2 (2-Isopropoxy-5-Methyl-4-Piperidin 4-Yl-Phenyl)-N4-2-(Propane-2- Sulfonyl)- henylPyrimidine-2, 4-Damine. 2016.

Journal Pre-proof

133. 134.

135. 136. 137. 138. 139. 140. 141.

142. 143. 144. 145. 146.

of

ro

132.

-p

131.

re

130.

lP

129.

na

128.

ur

125. 126. 127.

EMA, Gefitinib Mylan - Assessment Report. 2018. Angira, D., et al., Exploring a solvated dimer of Gefitinib: a quantitative analysisThis article is dedicated to Professor K. S. Viswanathan in celebration of his 65th birthday. Acta Crystallographica Section C, 2018. 74(8): p. 944-950. EMA, Zelboraf - Vemurafenib - Assesment Report. 2012. FDA, Highlights of Prescribing Information - ZELBORAF® (vemurafenib) tablets. 2017. Charman, W.N., et al., Physicochemical and physiological mechanisms for the effects of food on drug absorption: The role of lipids and pH. 1997. 86(3): p. 269-282. Evans, D.F., et al., Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut, 1988. 29(8): p. 1035-41. Kataoka, M., et al., Effects of gastric pH on oral drug absorption: In vitro assessment using a dissolution/permeation system reflecting the gastric dissolution process. Eur J Pharm Biopharm, 2016. 101: p. 103-11. Ewe, K., et al., Inflammation does not decrease intraluminal pH in chronic inflammatory bowel disease. Dig Dis Sci, 1999. 44(7): p. 1434-9. Press, A.G., et al., Gastrointestinal pH profiles in patients with inflammatory bowel disease. Aliment Pharmacol Ther, 1998. 12(7): p. 673-8. Dressman, J.B., et al., Upper gastrointestinal (GI) pH in young, healthy men and women. Pharm Res, 1990. 7(7): p. 756-61. Mudie, D.M., G.L. Amidon, and G.E. Amidon, Physiological Parameters for Oral Delivery and In vitro Testing. Molecular pharmaceutics, 2010. 7(5): p. 1388-1405. B Shekhawat, P. and V. B Pokharkar, Understanding peroral absorption: regulatory aspects and contemporary approaches to tackling solubility and permeability hurdles. Acta pharmaceutica Sinica. B, 2017. 7(3): p. 260-280. Zain, W.M. and W.N. I’zzah, In vitro and in vivo models to assess the mechanism of lapatinibinduced diarrhoea. 2016. EMA, Sprycel - Dasatinib - Scientific Discussion. 2006. Santana, D.P.d., et al., Reversed phase HPLC determination of tamoxifen in dog plasma and its pharmaco-kinetics after a single oral dose administration. Química Nova, 2008. 31(1): p. 47-52. SreeHarsha, N., et al., An Approach to Enhance Dissolution Rate of Tamoxifen Citrate. BioMed Research International, 2019. 2019: p. 1-11. Fellner, C., Vismodegib (erivedge) for advanced Basal cell carcinoma. P & T : a peer-reviewed journal for formulary management, 2012. 37(12): p. 670-682. EMA, Tasigna - Nilotinib - Scientific Discussion. 2007. Sieger, P., Y. Cui, and S. Scheuerer, pH-dependent solubility and permeability profiles: A useful tool for prediction of oral bioavailability. European Journal of Pharmaceutical Sciences, 2017. 105: p. 82-90. Michael Aulton, K.T., Aulton's Pharmaceutics E-Book: The Design and Manufacture of Medicines. 2017: Elsevier Health Sciences. Löf, K., et al., Kinetics of chlorambucil in vitro: effects of fluid matrix, human gastric juice, plasma proteins and red cells. Chemico-Biological Interactions, 1997. 103(3): p. 187-198. Wassermann, K. and H. Bundgaard, Kinetics of the acid-catalyzed hydrolysis of doxorubicin. International Journal of Pharmaceutics, 1983. 14(1): p. 73-78. Khulbe, P., et al., In-situ buffered formulation: an effective approach for acid labile drug. International Journal of Pharmaceutical Sciences and Research, 2017. 8(1): p. 35. Beijnen, J.H., et al., Degradation kinetics of etoposide in aqueous solution. International Journal of Pharmaceutics, 1988. 41(1): p. 169-178.

Jo

123. 124.

Journal Pre-proof

154. 155.

156.

157.

158.

159. 160. 161.

162. 163. 164. 165. 166. 167.

of

ro

153.

-p

152.

re

151.

lP

150.

na

149.

ur

148.

Raghuvanshi, D., et al., Stability study on an anti-cancer drug 4-(3,5-bis(2-chlorobenzylidene)-4oxo-piperidine-1-yl)-4-oxo-2-butenoic acid (CLEFMA) using a stability-indicating HPLC method. Journal of pharmaceutical analysis, 2017. 7(1): p. 1-9. Gokhale, M., A. Thakur, and F. Rinaldi, Degradation of BMS-753493, a novel epothilone folate conjugate anticancer agent. Drug Development and Industrial Pharmacy, 2013. 39(9): p. 13151327. de Man, F., et al., Drug–drug interactions in patients treated for cancer: a prospective study on clinical interventions†. Annals of Oncology, 2015. 26(5): p. 992-997. Rogala, B.G., et al., Oral Anticancer Therapy: Management of Drug Interactions. Journal of oncology practice, 2019. 15(2): p. 81-90. Scripture, C.D. and W.D. Figg, Drug interactions in cancer therapy. Nature Reviews Cancer, 2006. 6(7): p. 546-558. Budha, N.R., et al., Drug Absorption Interactions Between Oral Targeted Anticancer Agents and PPIs: Is pH-Dependent Solubility the Achilles Heel of Targeted Therapy? 2012. 92(2): p. 203-213. ter Heine, R., et al., Erlotinib and pantoprazole: a relevant interaction or not? British Journal of Clinical Pharmacology, 2010. 70(6): p. 908-911. Eley, T., et al., Phase I Study of the Effect of Gastric Acid pH Modulators on the Bioavailability of Oral Dasatinib in Healthy Subjects. 2009. 49(6): p. 700-709. Yokota, H., et al., Effects of Histamine 2-receptor Antagonists and Proton Pump Inhibitors on the Pharmacokinetics of Gefitinib in Patients With Non–small-cell Lung Cancer. Clinical Lung Cancer, 2017. 18(6): p. e433-e439. Abbas, R., C. Leister, and D. Sonnichsen, A Clinical Study to Examine the Potential Effect of Lansoprazole on the Pharmacokinetics of Bosutinib when Administered Concomitantly to Healthy Subjects. Clinical Drug Investigation, 2013. 33(8): p. 589-595. McAlister, R.K., et al., Effect of Concomitant pH-Elevating Medications with Pazopanib on Progression-Free Survival and Overall Survival in Patients with Metastatic Renal Cell Carcinoma. Oncologist, 2018. 23(6): p. 686-692. Mir, O., et al., Impact of Concomitant Administration of Gastric Acid–Suppressive Agents and Pazopanib on Outcomes in Soft-Tissue Sarcoma Patients Treated within the EORTC 62043/62072 Trials. 2019. 25(5): p. 1479-1485. Li, R., et al., Abiraterone inhibits 3beta-hydroxysteroid dehydrogenase: a rationale for increasing drug exposure in castration-resistant prostate cancer. Clin Cancer Res, 2012. 18(13): p. 3571-9. Basa-Denes, O., et al., Investigations of the mechanism behind the rapid absorption of nanoamorphous abiraterone acetate. Eur J Pharm Sci, 2019. 129: p. 79-86. Stappaerts, J., et al., Rapid conversion of the ester prodrug abiraterone acetate results in intestinal supersaturation and enhanced absorption of abiraterone: in vitro, rat in situ and human in vivo studies. Eur J Pharm Biopharm, 2015. 90: p. 1-7. EMA, Stivarga - Regorafenib - Assesment Report. 2013. van Leeuwen, R.W., et al., Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol, 2014. 15(8): p. e315-26. Thanki, K., et al., Oral delivery of anticancer drugs: Challenges and opportunities. Journal of Controlled Release, 2013. 170(1): p. 15-40. Misaka, S., F. Müller, and M.F. Fromm, Clinical relevance of drug efflux pumps in the gut. Current Opinion in Pharmacology, 2013. 13(6): p. 847-852. Mitchell, M.D., The Role of Intestinal Efflux Transporters In Drug Absorption. 2013. Saneja, A., et al., Advances in P-glycoprotein-based approaches for delivering anticancer drugs: pharmacokinetic perspective and clinical relevance. Expert Opin Drug Deliv, 2014. 11(1): p. 12138.

Jo

147.

Journal Pre-proof

176. 177. 178. 179. 180.

181.

182. 183. 184. 185. 186. 187.

188.

of

175.

ro

174.

-p

173.

re

172.

lP

171.

na

170.

ur

169.

Lagas, J.S., et al., P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 determine the pharmacokinetics of etoposide. Clin Cancer Res, 2010. 16(1): p. 130-40. Miyazaki, M., et al., Pharmacokinetic assessment of absorptive interaction of oral etoposide and morphine in rats. Biol Pharm Bull, 2014. 37(3): p. 371-7. Breedveld, P., J.H. Beijnen, and J.H.M. Schellens, Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs. Trends in Pharmacological Sciences, 2006. 27(1): p. 17-24. Mao, Q. and J.D. Unadkat, Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update. The AAPS Journal, 2015. 17(1): p. 65-82. Hussaarts, K.G.A.M., et al., Clinically relevant drug interactions with multikinase inhibitors: a review. Therapeutic Advances in Medical Oncology, 2019. 11: p. 1758835918818347. Chen, Z., et al., Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Letters, 2016. 370(1): p. 153-164. Yang, Z., The Roles of Membrane Transporters on the Oral Drug Absorption. Journal of Molecular Pharmaceutics & Organic Process Research, 2013. 1(1). Gavhane, Y.N. and A.V. Yadav, Loss of orally administered drugs in GI tract. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society, 2012. 20(4): p. 331344. Barthe, L., J. Woodley, and G. Houin, Gastrointestinal absorption of drugs: methods and studies. Fundam Clin Pharmacol, 1999. 13(2): p. 154-68. Shen, D.D., K.L. Kunze, and K.E. Thummel, Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv Drug Deliv Rev, 1997. 27(2-3): p. 99-127. de Jong, J., et al., Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants. 2015. 3(4): p. e00156. Li, J., et al., CYP3A Phenotyping Approach to Predict Systemic Exposure to EGFR Tyrosine Kinase Inhibitors. JNCI: Journal of the National Cancer Institute, 2006. 98(23): p. 1714-1723. Christiansen, S.R., et al., Pharmacokinetics of erlotinib for the treatment of high-grade glioma in a pediatric patient with cystic fibrosis: case report and review of the literature. Pharmacotherapy, 2009. 29(7): p. 858-866. Kruijtzer, C., J. Beijnen, and J.J.T.o. Schellens, Improvement of oral drug treatment by temporary inhibition of drug transporters and/or cytochrome P450 in the gastrointestinal tract and liver: an overview. 2002. 7(6): p. 516-530. Rudek, M.A., et al., Handbook of Anticancer Pharmacokinetics and Pharmacodynamics. Second;2nd 2014; ed. 2014, New York, NY: Springer Verlag. Schulz, M., et al., The pharmacokinetics of flutamide and its major metabolites after a single oral dose and during chronic treatment. Eur J Clin Pharmacol, 1988. 34(6): p. 633-6. Shin, S.C., J.S. Choi, and X. Li, Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats. Int J Pharm, 2006. 313(1-2): p. 144-9. Hiles, J.J. and J.M. Kolesar, Role of sunitinib and sorafenib in the treatment of metastatic renal cell carcinoma. American Journal of Health-System Pharmacy, 2008. 65(2): p. 123-131. Dulucq, S. and M. Krajinovic, The pharmacogenetics of imanitib. Genome medicine, 2010. 2(11): p. 85-85. Yokomasu, A., et al., Effect of Intestinal and Hepatic First-pass Extraction on the Pharmacokinetics of Everolimus in Rats. Drug Metabolism and Pharmacokinetics, 2008. 23(6): p. 469-475. Marqus, S., E. Pirogova, and T.J.J.J.o.B.S. Piva, Evaluation of the use of therapeutic peptides for cancer treatment. 2017. 24(1): p. 21.

Jo

168.

Journal Pre-proof

196.

197. 198. 199. 200. 201. 202. 203. 204.

205. 206.

207.

208.

209.

of

ro

195.

-p

194.

re

193.

lP

192.

na

191.

ur

190.

Thundimadathil, J., Cancer treatment using peptides: current therapies and future prospects. Journal of amino acids, 2012. 2012: p. 967347-967347. Schwenger, E., et al., Harnessing Meta‐analysis to Refine an Oncology Patient Population for Physiology‐Based Pharmacokinetic Modeling of Drugs. Clinical Pharmacology & Therapeutics, 2018. 103(2): p. 271-280. Deenen, M.J., et al., Part 2: pharmacogenetic variability in drug transport and phase I anticancer drug metabolism. 2011. 16(6): p. 820-834. Nguyen, L., et al., Pharmacokinetic (PK) drug interaction studies of cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effect of cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK. 2015. 55(9): p. 1012-1023. Yang, Y.-h., et al., Enzyme-mediated hydrolytic activation of prodrugs. Acta Pharmaceutica Sinica B, 2011. 1(3): p. 143-159. Giacomini, K.M., et al., Membrane transporters in drug development. Nature Reviews Drug Discovery, 2010. 9: p. 215. Choi, K.E., et al., Plasma pharmacokinetics of high-dose oral melphalan in patients treated with trialkylator chemotherapy and autologous bone marrow reinfusion. Cancer Res, 1989. 49(5): p. 1318-21. Xie, Y., Y. Hu, and D.E. Smith, The proton‐coupled oligopeptide transporter 1 plays a major role in the intestinal permeability and absorption of 5‐aminolevulinic acid. British Journal of Pharmacology, 2016. 173(1): p. 167-176. Wang, C.-Y., et al., Regulation profile of the intestinal peptide transporter 1 (PepT1). Drug design, development and therapy, 2017. 11: p. 3511-3517. Porat, D. and A. Dahan, Active intestinal drug absorption and the solubility-permeability interplay. International Journal of Pharmaceutics, 2018. 537(1): p. 84-93. Choi, J.H. and C.M. Ko, Food and Drug Interactions. Journal of lifestyle medicine, 2017. 7(1): p. 19. Segal, E.M., et al., Oral Chemotherapy Food and Drug Interactions: A Comprehensive Review of the Literature. 2014. 10(4): p. e255-e268. Chien, C., M. Smith, and P.J.I.j.o.P. De Porre, Effect of food on abiraterone pharmacokinetics: a review. 2017. 2(3): p. 183-193. Pithavala, Y.K., et al., Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers. 2012. 70(1): p. 103-112. FDA, Bosulif - Bosutinib - Clinical Pharmacology And Biopharmaceutics Review. 2011. Nguyen, L., et al., Evaluation of the effect of food and gastric pH on the single-dose pharmacokinetics of cabozantinib in healthy adult subjects. J Clin Pharmacol, 2015. 55(11): p. 1293-302. Lau, Y.Y., et al., Effects of meal type on the oral bioavailability of the ALK inhibitor ceritinib in healthy adult subjects. J Clin Pharmacol, 2016. 56(5): p. 559-66. Ouellet, D., et al., Effects of particle size, food, and capsule shell composition on the oral bioavailability of dabrafenib, a BRAF inhibitor, in patients with BRAF mutation-positive tumors. 2013. 102(9): p. 3100-3109. Ling, J., et al., Effect of food on the pharmacokinetics of erlotinib, an orally active epidermal growth factor receptor tyrosine-kinase inhibitor, in healthy individuals. Anti-Cancer Drugs, 2008. 19(2): p. 209-216. Koch, K.M., et al., Effects of food on the relative bioavailability of lapatinib in cancer patients. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2009. 27(8): p. 1191-1196. EMA, Rydapt - Midostaurin - Summary of Product Characterisrics. 2017.

Jo

189.

Journal Pre-proof

219.

220.

221.

222. 223. 224. 225.

226. 227.

228.

229. 230.

of

ro

218.

-p

217.

re

216.

lP

214. 215.

na

213.

ur

212.

FDA, Multi-Discipline Review - NERLYNX (neratinib). 2016. Tian, X., et al., Clinical Pharmacokinetic and Pharmacodynamic Overview of Nilotinib, a Selective Tyrosine Kinase Inhibitor. 2018. 58(12): p. 1533-1540. Schmid, U., et al., Population pharmacokinetics of nintedanib, an inhibitor of tyrosine kinases, in patients with non-small cell lung cancer or idiopathic pulmonary fibrosis. Cancer chemotherapy and pharmacology, 2018. 81(1): p. 89-101. Verheijen, R.B., et al., Clinical Pharmacokinetics and Pharmacodynamics of Pazopanib: Towards Optimized Dosing. Clinical pharmacokinetics, 2017. 56(9): p. 987-997. EMA, Odomzo - Sonidegib - Assesment Report. 2015. Cox, D.S., et al., Evaluation of the Effects of Food on the Single‐Dose Pharmacokinetics of Trametinib, a First‐in‐Class MEK Inhibitor, in Patients with Cancer. The Journal of Clinical Pharmacology, 2013. 53(9): p. 946-954. Colomer, R., et al., Treatment of cancer with oral drugs: a position statement by the Spanish Society of Medical Oncology (SEOM). Annals of oncology : official journal of the European Society for Medical Oncology, 2010. 21(2): p. 195-198. Wilkinson, G.R., The effects of diet, aging and disease-states on presystemic elimination and oral drug bioavailability in humans. Adv Drug Deliv Rev, 1997. 27(2-3): p. 129-159. Given, B.A., et al., Medication Burden of Treatment Using Oral Cancer Medications. Asia-Pacific journal of oncology nursing, 2017. 4(4): p. 275-282. Juric, D., et al., A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kalpha Isoform Inhibitor, in Patients with Advanced Solid Malignancies. Clin Cancer Res, 2017. 23(17): p. 5015-5023. Durak, L., et al., Development and Scale-Up of a Crystallization Process To Improve an API’s Physiochemical and Bulk Powder Properties. Organic Process Research & Development, 2018. 22(3): p. 296-305. Patel, C.G., et al., Characterizing the Sources of Pharmacokinetic Variability for TAK-117 (Serabelisib), an Investigational Phosphoinositide 3-Kinase Alpha Inhibitor: A Clinical Biopharmaceutics Study to Inform Development Strategy. Clin Pharmacol Drug Dev, 2018. Routes, A.E., DRUG ABSORPTION, DISTRIBUTION AND ELIMINATION; PHARMACOKINETICS. 2015. Sawicki, E., Solid dispersions in oncology: a solution to solubility-limited oral drug absorption. 2017. FDA, Highlights of Prescribing Information - Docetaxel; injection concentrate. 2016. Chen, Y., et al., Development of a Solid Supersaturatable Self-Emulsifying Drug Delivery System of Docetaxel with Improved Dissolution and Bioavailability. Biological and Pharmaceutical Bulletin, 2011. 34(2): p. 278-286. Lim, S.M., et al., Enhancement of docetaxel solubility using binary and ternary solid dispersion systems. Drug Dev Ind Pharm, 2015. 41(11): p. 1847-55. Sawicki, E., et al., Pharmaceutical development of an oral tablet formulation containing a spray dried amorphous solid dispersion of docetaxel or paclitaxel. International Journal of Pharmaceutics, 2016. 511(2): p. 765-773. Moes, J.J., et al., Pharmaceutical development and preliminary clinical testing of an oral solid dispersion formulation of docetaxel (ModraDoc001). International Journal of Pharmaceutics, 2011. 420(2): p. 244-250. Chen, Y., et al., Preparation and characterization of emulsified solid dispersions containing docetaxel. 2011. 34(11): p. 1909-1917. Piao, H., et al., A pre-formulation study of a polymeric solid dispersion of paclitaxel prepared using a quasi-emulsion solvent diffusion method to improve the oral bioavailability in rats. Drug Development and Industrial Pharmacy, 2016. 42(3): p. 353-363.

Jo

210. 211.

Journal Pre-proof

235. 236.

237. 238. 239.

243. 244.

245. 246. 247. 248. 249.

ur

242.

Jo

241.

na

lP

240.

of

234.

ro

233.

-p

232.

Andrews, G.P., O.A. AbuDiak, and D.S. Jones, Physicochemical Characterization of Hot Melt Extruded Bicalutamide–Polyvinylpyrrolidone Solid Dispersions. Journal of Pharmaceutical Sciences, 2010. 99(3): p. 1322-1335. Ren, F., et al., Characteristics of Bicalutamide Solid Dispersions and Improvement of the Dissolution. Drug Development and Industrial Pharmacy, 2006. 32(8): p. 967-972. Abu-Diak, O.A., D.S. Jones, and G.P. Andrews, Understanding the Performance of Melt-Extruded Poly(ethylene oxide)–Bicalutamide Solid Dispersions: Characterisation of Microstructural Properties Using Thermal, Spectroscopic and Drug Release Methods. Journal of Pharmaceutical Sciences, 2012. 101(1): p. 200-213. Sancheti, P.P., et al., Development and characterization of bicalutamide-poloxamer F68 solid dispersion systems. Pharmazie, 2008. 63(8): p. 571-5. Srikanth, M., et al., In-vitro dissolution rate enhancement of poorly water soluble non-steroidal antiandrogen agent, bicalutamide, with hydrophilic carriers. 2010. Szafraniec, J., et al., The Self-Assembly Phenomenon of Poloxamers and Its Effect on the Dissolution of a Poorly Soluble Drug from Solid Dispersions Obtained by Solvent Methods. Vol. 11. 2019. 130. Grebernar, I.R., Marina; MUNDORFER, Tina ; NEZIC, Igor SOLID STATE FORMS OF CERITINIB AND SALTS THEREOF. 2015. Peddy, V.N.S., Pure amorphous and amorphous solid dispersion of ceritinib. 2015. Wilson, V., et al., Relationship between amorphous solid dispersion in vivo absorption and in vitro dissolution: phase behavior during dissolution, speciation, and membrane mass transport. Journal of Controlled Release, 2018. 292: p. 172-182. Shepard, K.B., ; and M. Morgen. Sustained Supersaturation of Erlotinib Sdd Ternary Amorphous Systems. Pharmaceutical Development-Pharmaceutical Engineering & Drug Delivery 2017 5/30/2019]; Available from: https://www.aiche.org/conferences/aiche-annualmeeting/2017/proceeding/paper/14a-sustained-supersaturation-erlotinib-sdd-ternaryamorphous-systems. Shah, J.C., J.R. Chen, and D. Chow, Preformulation study of etoposide: II. Increased solubility and dissolution rate by solid-solid dispersions. International Journal of Pharmaceutics, 1995. 113(1): p. 103-111. Song, Y., et al., Acid–Base Interactions of Polystyrene Sulfonic Acid in Amorphous Solid Dispersions Using a Combined UV/FTIR/XPS/ssNMR Study. Molecular Pharmaceutics, 2016. 13(2): p. 483-492. Herbrink, M., et al., Improving the solubility of nilotinib through novel spray-dried solid dispersions. Int J Pharm, 2017. 529(1-2): p. 294-302. Li, S., et al., Development and in-vivo assessment of the bioavailability of oridonin solid dispersions by the gas anti-solvent technique. International Journal of Pharmaceutics, 2011. 411(1): p. 172-177. Abdal-Hammid, S. and h. hussein abduljabbar, Enhancement of the solubility and the dissolution rate of tamoxifen citrate solid dispersion using soluplus by solvent evaporation technique. 2019. Chowdhury, N., et al., Development of Hot Melt Extruded Solid Dispersion of Tamoxifen Citrate and Resveratrol for Synergistic Effects on Breast Cancer Cells. 2018. 19(7): p. 3287-3297. Szafraniec, J., et al., Molecular Disorder of Bicalutamide-Amorphous Solid Dispersions Obtained by Solvent Methods. Pharmaceutics, 2018. 10(4): p. 194. Tres, F., et al., Monitoring the Dissolution Mechanisms of Amorphous Bicalutamide Solid Dispersions via Real-Time Raman Mapping. Mol Pharm, 2015. 12(5): p. 1512-22. Van Nuffel, A.M.T., et al., Repurposing Drugs in Oncology (ReDO)—clarithromycin as an anticancer agent. ecancermedicalscience, 2015. 9: p. 513.

re

231.

Journal Pre-proof

257. 258. 259. 260.

261.

262.

263.

264. 265.

266. 267. 268. 269.

of

ro

256.

-p

255.

re

254.

lP

253.

na

252.

ur

251.

Chu, S.Y., R. Deaton, and J. Cavanaugh, Absolute bioavailability of clarithromycin after oral administration in humans. Antimicrobial Agents and Chemotherapy, 1992. 36(5): p. 1147-1150. Rajinikanth, P.S., et al., Formulation and Evaluation of Clarithromycin Microspheres for Eradication of Helicobacter pylori. Chemical and Pharmaceutical Bulletin, 2008. 56(12): p. 1658-1664. Pereira, J.M., et al., Interplay of Degradation, Dissolution and Stabilization of Clarithromycin and Its Amorphous Solid Dispersions. Molecular Pharmaceutics, 2013. 10(12): p. 4640-4653. Beijnen, J.H. and J.H.M. Schellens, Drug interactions in oncology. The Lancet Oncology, 2004. 5(8): p. 489-496. Clarke, S.J. and L.P. Rivory, Clinical pharmacokinetics of docetaxel. Clin Pharmacokinet, 1999. 36(2): p. 99-114. Song, C.K., I.-S. Yoon, and D.-D. Kim, Poloxamer-based solid dispersions for oral delivery of docetaxel: Differential effects of F68 and P85 on oral docetaxel bioavailability. International Journal of Pharmaceutics, 2016. 507(1): p. 102-108. Miao, L., et al., Effect of supersaturation on the oral bioavailability of paclitaxel/polymer amorphous solid dispersion. Drug Deliv Transl Res, 2019. 9(1): p. 344-356. Athenex. Orascovery Platform. 05/27/2019]; Available from: https://www.athenex.com/oncology-innovation/oral-absorption-platform/. Shanmugam, S., et al., Enhanced oral bioavailability of paclitaxel by solid dispersion granulation. Drug Development and Industrial Pharmacy, 2015. 41(11): p. 1864-1876. Miller, D.A., et al., Bioavailability enhancement of a BCS IV compound via an amorphous combination product containing ritonavir. 2016. 68(5): p. 678-691. Park, Y.S., et al., Acetyl-11-keto-beta-boswellic acid (AKBA) is cytotoxic for meningioma cells and inhibits phosphorylation of the extracellular-signal regulated kinase 1 and 2. Adv Exp Med Biol, 2002. 507: p. 387-93. Beig, A., et al., Concomitant solubility-permeability increase: Vitamin E TPGS vs. amorphous solid dispersion as oral delivery systems for etoposide. European Journal of Pharmaceutics and Biopharmaceutics, 2017. 121: p. 97-103. Kaur, S., et al., Freeze dried solid dispersion of exemestane: A way to negate an aqueous solubility and oral bioavailability problems. European Journal of Pharmaceutical Sciences, 2017. 107: p. 54-61. Eedara, B.B. and S. Bandari, Lipid-based dispersions of exemestane for improved dissolution rate and intestinal permeability: in vitro and ex vivo characterization. Artificial Cells, Nanomedicine, and Biotechnology, 2017. 45(5): p. 917-927. Eedara, B.B., et al., Enhanced solubility and permeability of exemestane solid dispersion powders for improved oral delivery. 2013. 43(3): p. 229-242. FDA. Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA DRAFT GUIDANCE. 2013 09/09/2018]; Available from: https://www.fda.gov/downloads/drugs/guidances/ucm377465.pdf. Undevia, S.D., G. Gomez-Abuin, and M.J. Ratain, Pharmacokinetic variability of anticancer agents. Nature Reviews Cancer, 2005. 5: p. 447. Sparreboom, A. and J. Verweij, Advances in Cancer Therapeutics. Clinical pharmacology and therapeutics, 2009. 85(2): p. 113-117. Tong, Y., et al., Abstract 614: Proxalutamide (GT0918), a potent androgen receptor pathway inhibitor. 2014. 74(19 Supplement): p. 614-614. Yang, M., et al., Microenvironmental pH-modified solid dispersions to enhance the dissolution and bioavailability of poorly water-soluble weakly basic GT0918, a developing anti-prostate

Jo

250.

Journal Pre-proof

273. 274. 275.

276.

281.

282.

283. 284. 285. 286. 287. 288.

na

280.

ur

279.

Jo

278.

lP

re

277.

of

272.

ro

271.

-p

270.

cancer drug: Preparation, characterization and evaluation in vivo. International Journal of Pharmaceutics, 2014. 475(1): p. 97-109. Solymosi, T., et al., Novel formulation of abiraterone acetate might allow significant dose reduction and eliminates substantial positive food effect. 2017. 80(4): p. 723-728. Truong, D.H., et al., Development of Solid Self-Emulsifying Formulation for Improving the Oral Bioavailability of Erlotinib. 2016. 17(2): p. 466-473. Wagner, J.G., Linear pharmacokinetic equations allowing direct calculation of many needed pharmacokinetic parameters from the coefficients and exponents of polyexponential equations which have been fitted to the data. Journal of Pharmacokinetics Biopharmaceutics, 1976. 4(5): p. 443-467. Chen, H., et al., Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer. Oncol Lett, 2017. 14(4): p. 4349-4354. Sawicki, E., et al., Clinical pharmacokinetics of an amorphous solid dispersion tablet of elacridar. 2017. 7(1): p. 125-131. Sawicki, E., et al., Pharmaceutical development of an amorphous solid dispersion formulation of elacridar hydrochloride for proof-of-concept clinical studies. Drug Development and Industrial Pharmacy, 2017. 43(4): p. 584-594. Peng, S.-B., et al., Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Antitumor Activities in RAS or BRAF Mutant Cancers. Cancer Cell, 2015. 28(3): p. 384-398. Henry, J.R., et al., Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against BRAF or RAS Mutant Tumor Cells. Journal of Medicinal Chemistry, 2015. 58(10): p. 4165-4179. Evans, W.E. and M.V.J.C.P. Relling, Clinical Pharmacokinetics-Pharmacodynamics of Anticancer Drugs. 1989. 16(6): p. 327-336. Evans, W.E.J.B., Clinical pharmacodynamics of anticancer drugs: a basis for extending the concept of dose-intensity. J Blut, 1988. 56(6): p. 241-248. Xu, X.S., et al., Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer. Clin Pharmacokinet, 2017. 56(1): p. 55-63. Xu, X.S., et al., Correlation between Prostate-Specific Antigen Kinetics and Overall Survival in Abiraterone Acetate-Treated Castration-Resistant Prostate Cancer Patients. Clin Cancer Res, 2015. 21(14): p. 3170-7. Carton, E., et al., Relation between plasma trough concentration of abiraterone and prostatespecific antigen response in metastatic castration-resistant prostate cancer patients. Eur J Cancer, 2017. 72: p. 54-61. Housman, G., et al., Drug Resistance in Cancer: An Overview. Cancers, 2014. 6(3): p. 1769-1792. Godugu, C., et al., Novel Gefitinib Formulation with Improved Oral Bioavailability in Treatment of A431 Skin Carcinoma. Pharmaceutical research, 2016. 33(1): p. 137-154. Shanholtz, C., Acute life-threatening toxicity of cancer treatment. Crit Care Clin, 2001. 17(3): p. 483-502. FDA, Highlights of Prescribing Information - NEXAVAR (sorafenib) tablets. 2010. Barea, S.A., et al., Solid dispersions enhance solubility, dissolution, and permeability of thalidomide. Drug Development and Industrial Pharmacy, 2017. 43(3): p. 511-518. Maincent, J. and R.O. Williams, 3rd, Sustained-release amorphous solid dispersions. Drug Deliv Transl Res, 2018.

Journal Pre-proof

300.

301.

302. 303. 304.

of

ro

-p

299.

re

297. 298.

lP

295. 296.

na

294.

ur

290. 291. 292. 293.

Liu, H., et al., A high bioavailability and sustained-release nano-delivery system for nintedanib based on electrospray technology. International journal of nanomedicine, 2018. 13: p. 83798393. FDA, Highlights of Prescribing Information - AFINITOR (everolimus) tablets. 2010. FDA, Highlights of Prescribing Information - STIVARGA (regorafenib) tablets. 2012. FDA, Highlights of Prescribing Information - VENCLEXTA® (venetoclax) tablets. 2016. Birtalan, E., et al., Melt-extruded Solid Dispersions Containing An Apoptosis-inducing Agent. 2012. Zhou, D., et al., Bridging Olaparib Capsule and Tablet Formulations Using Population Pharmacokinetic Meta-analysis in Oncology Patients. J Clinical Pharmacokinetics, 2019. 58(5): p. 615-625. EMA, Lynparza - Olaparib - Assesment Report. 2018. He, Y. and C. Ho, Amorphous Solid Dispersions: Utilization and Challenges in Drug Discovery and Development. Journal of Pharmaceutical Sciences, 2015. 104(10): p. 3237-3258. FDA, Zelboraf - Vemurafenib - Clinical Pharmacology And Biopharmaceutics Review. 2011. Ellenberger, D.J., et al., Improved Vemurafenib Dissolution and Pharmacokinetics as an Amorphous Solid Dispersion Produced by KinetiSol® Processing. AAPS PharmSciTech, 2018. 19(5): p. 1957-1970. Breitkreutz, M.M.P.S.J., Dissolution Behavior of Regorafenib Amorphous Solid Dispersion Under Biorelevant Conditions 2019: 3rd European Conference on Pharmaceutics, 25th-26th March 2019, Bologna, Italy. Jang, S.W. and M.J. Kang, Improved oral absorption and chemical stability of everolimus via preparation of solid dispersion using solvent wetting technique. International Journal of Pharmaceutics, 2014. 473(1-2): p. 187-193. Jang, S.W., Y.W. Choi, and M.J. Kang, Preparation of solid dispersion of Everolimus in Gelucire 50/13 using melt granulation technique for enhanced drug release. J Bull Korean Chem Soc, 2014. 35(7): p. 1939. Haser, A., et al., Melt Extrusion, in Formulating Poorly Water Soluble Drugs, R.O. Williams Iii, A.B. Watts, and D.A. Miller, Editors. 2016, Springer International Publishing: Cham. p. 383-435. FDA, Highlights of Prescribing Information - LYNPARZA® (olaparib) tablets. 2017. Rolfo, C., et al., Effect of Food on the Pharmacokinetics of Olaparib after Oral Dosing of the Capsule Formulation in Patients with Advanced Solid Tumors. Adv Ther, 2015. 32(6): p. 510-22.

Jo

289.

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Figure 3

Figure 4

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Figure 6

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