Oral delivery of anticancer drugs I: general considerations

Drug Discovery Today  Volume 00, Number 00  September 2012

REVIEWS

Oral delivery of anticancer drugs I: general considerations Silvia Mazzaferro, Kawthar Bouchemal and Gilles Ponchel Universite´ Paris-Sud, Faculte´ de Pharmacie, UMR CNRS 8612, Institut Galien Paris-Sud, 5, rue J.B. Cle´ment, 92296 Chaˆtenay-Malabry Cedex, France

Historically, most of anticancer drugs were delivered by the intravenous route which is the most direct one leading to immediate and complete bioavailability of the drugs. However, this administration route could result in several side effects and requires a clinic or hospitalization visit, nursing and palliative treatment. For these latter reasons, oral delivery of anticancer drugs is nowadays more and more considered, including already marketed drugs. In this first review, we aim to identify general considerations for the oral delivery of anticancer drugs. In the second and the third reviews we respectively discuss the prodrug strategy and the use of drug delivery systems to improve the oral bioavailability of anticancer drugs.

Anticancer therapy is one of the three pillars of cancer treatment along with surgical treatment and radiation therapy. Generally, anticancer drugs are divided into three categories: cytotoxic, biological and hormonal agents. Cytotoxic agents are the traditional therapies that damage cancer cells by interfering with DNA or its precursor, inhibiting the cellular division. However, this kind of agents has the great drawback of killing healthy cells along with cancer cells [1]. Major types of cytotoxic agents include alkylating agents [2,3], antimetabolites [4] and plant alkaloid [5– 7]. Biological agents or targeted agents include monoclonal antibodies [8–12] and cancer vaccines [13–16]. This therapy (also called immunotherapy, biological response modifier therapy, or biotherapy) uses the body’s immune system to treat cancer. Hormonal therapy interferes with hormone-dependent pathways that promote the development or the growth of cancer cells and has an important role in treating breast and prostate cancers. It includes tamoxifen [17,18] and aromatase inhibitors [19–21]. At present, most anticancer drugs are administered intravenously (i.v.). The intravenous route is the most direct one and overcomes the variable absorption patterns of the gastrointestinal tract. It leads to immediate and complete bioavailability and therefore, accurate dosing. However, this route could be hazardous, because high concentration of the drug is delivered to normal tissues [22,23]. I.v. chemotherapy regimens are designed to deliver the maximal tolerated dose of cytotoxic agent to kill cancer cells in a short period of therapy followed by a period of several weeks without administration [24]. Cisplatin, for example, since 1979 has become an important

Dr Silvia Mazzaferro obtained her master degree in chemistry and pharmaceutical technology at the University of Camerino (Italy) in 2008. During her university studies she joined the Erasmus Program for an internship at the University of Paris South ‘Institut Galien Paris Sud’ in France from 2007 to 2008. In 2011 she obtained her PhD in biopharmacy and pharmaceutical technology focusing on novel nanosized polymeric delivery systems for the improvement of the oral bioavailability of anticancer drugs. Since 2012 she is a postdoctoral researcher at the ‘Laboratoire de chimie des Polyme`res Organique’ in Bordeaux, France and she is developing new polysaccharide-based nanocarriers for lung cancer treatment. Dr Kawthar Bouchemal is an associate professor of pharmaceutical technology at the University of Paris South ‘Institut Galien Paris Sud’ since 2006. During her PhD thesis she acquired a solid foundation in the domain of colloidal system formulation and the scale-up of their production. Her main topics of interest are designed to address challenges for: (i) the entrapment of poorly absorbed molecules, (ii) to make them bypass natural barriers and (iii) the conception and manufacturing of pilot-scale setups aiming to increase the size of colloidal system batches. She has directed ten master students and seven PhD students. She is the author and co-author of more than 41 publications and book chapters. Prof. Gilles Ponchel is full professor at the University of Paris-South since 2000, where he teaches pharmaceutical technology and biopharmacy. He is leading a multidisciplinary research team belonging to the Institut Galien Universite´ Paris-Sud and specialized in the field of drug delivery. The aim of the team is to conceive and to develop innovative drug delivery systems able to improve the crossing of active drugs through physico-chemical and biological barriers. His main research interests are: (i) the development and the evaluation of bioadhesive delivery systems and (ii) the conception of pharmaceutically acceptable multifunctionalized nanoparticles (tailored polymers, polypeptides, cyclodextrins, among others) for optimizing the interactions with living matter in the context of targeted applications. One of his specific interests is to gain a better understanding at the molecular level of the relationships between surface properties of nanoparticles and their capacities of interacting in the body, through various phenomena including bioadhesion. He is the author of over 100 research papers, more than 170 communications, more than 50 invited lectures, many book chapters and book co-authoring and 14 patents. He has directed 20 PhD students. Prof. Gilles Ponchel is also especially interested in the transfer of innovations to the pharmaceutical industry in the field of bioadhesive drug delivery systems.

Corresponding author:. Bouchemal, K. ([email protected]) www.drugdiscoverytoday.com 1 Please cite this article in press as: S.. Mazzaferro, et al., Oral delivery of anticancer drugs I: general considerations, Drug Discov Today (2012), http://dx.doi.org/10.1016/ j.drudis.2012.08.004

1359-6446/06/$ - see front matter ß 2012 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2012.08.004

Reviews  KEYNOTE REVIEW

This review highlights the general issues for the oral delivery of anticancer drugs.

DRUDIS-1084; No of Pages 10 REVIEWS

Reviews  KEYNOTE REVIEW

component in chemotherapy for its broad spectrum of antitumor activity. Unfortunately, this drug has several side effects because of its unspecific uptake into all rapidly dividing cells. For this reason, the tolerated doses are very low. The major side effects are nephrotoxicity, neurotoxicity, ototoxicity and myelosuppression [25]. In addition, the preparation of injectable formulations requires the use of specific pharmaceutical excipients, which may contribute to the toxicity of the final formulation. For example, paclitaxel (Taxol1), approved for breast, prostate and lung cancers, is highly lipophilic requiring a particular excipient for its formulation composed of 1:1 blend of Cremophor EL (polyethoxylated castor oil) and ethanol, diluted with 5- to 20-fold in normal saline or dextrose solution before administration. However, many problems were reported related to the large amount of Cremophor EL necessary to deliver the required dose of paclitaxel. This excipient causes several hypersensitivity reactions, nephrotoxicity and neurotoxicity. Consequently, premedication with corticosteroids and antihistamine is used to increase safety and reduce the intensity of these kinds of reactions [26]. Furthermore, it was reported that this additive could modify the kinetics of the drug [27,28]. In the same way, in Taxotere1, docetaxel is formulated with the non-ionic surfactant polysorbate 80 (Tween1 80) which has been implicated in the occurrence of severe anaphylactic hypersensitivity reactions [29]. Furthermore, i.v. chemotherapy requires a hospital visit, nursing, and a palliative treatment. Although the use of ambulatory pumps and indwelling catheters enable home-based i.v. chemotherapy, this kind of administration remains inconvenient for patients. It is painful, can lead to hemorrhage and in the long term it is often associated with infection, bleeding and venous thrombosis [30]. Generally, the patient shows sight of depression and anxiety he/she does not feel free and independent and his daily life is influenced by the medication schedule [31]. In this context, the oral chemotherapy becomes a very interesting alternative to the i.v. therapy. In several studies, patient preference for oral or i.v. treatment was studied directly in a randomized crossover trial, comparing an oral drug regimen versus i.v. treatment. The majority of patients at the end of the study chose to continue with the oral treatment. They found oral chemotherapy advantageous and it made them feel less sick. It helped them to face their illness better. The most important feeling elicited is the feeling of freedom. Patients can spend more time at home and the medication interfered less with the dailies activities. Finally, from an economical point of view, the oral therapy is convenient because it limits the cost of hospitalization and the infusion equipment supplies [22,30,32–34]. Currently, 10% of cancer chemotherapy is provided to patients as an oral formulation, but the National Comprehensive Cancer Network predicts that by the year 2013 this percentage will jump to 25% [35]. More than 20 are already available and some emerging oral cytotoxic agents are in development (Tables 1 and 2) [36]. Most of the oral anticancer drugs are not based on new molecules, but are new formulations of the drugs already used for i.v. therapy. In this review we discuss the general considerations related to oral chemotherapy, focusing on its potential benefits and limitations. Although the availability problems of the long-used cytotoxic drugs and the patient adherence represent two major aspects in view of new oral formulations, it is also important to consider their toxicity. 2

Drug Discovery Today  Volume 00, Number 00  September 2012

General issues for the oral delivery of anticancer drugs Nowadays we can find different kinds of anticancer drugs formulated for oral administration (Table 1). If we pay attention to the type of formulations used, we can notice that most of oral anticancer drugs are formulated as capsules or tablets. These pharmaceutical forms are simple, but are adapted to drugs with few problems of solubility and bioavailability. Nevertheless, it should be remarked that many anticancer drugs belong to the class IV of the Biopharmaceutical Classification System (BCS), which comprises substances with both low solubility in aqueous fluids and low apparent permeability. When foreseen oral delivery of these molecules, complex formulation issues should be addressed including (i) limited aqueous solubilities, (ii) degradation in gastrointestinal fluids, (iii) affinity for intestinal and liver cytochrome P450 (CYP3A4) and P-glycoprotein (P-gp) in the intestinal barrier [22] and (iv) poor intestinal permeabilities. For these reasons, the choice of the parenteral administration of this kind of drugs seems to be more obvious. Success in cancer treatment has traditionally been measured in terms of cure rate, increased survival and tumor response. In the early times of anticancer drug development, formulators did not wonder if an oral chemotherapy might be better than a parenteral treatment because the search for efficiency was paramount. After i.v. delivery the availability of the drug in the body is maximal because the drug is directly delivered into the bloodstream. On the contrary, after oral administration the compound must be released from the formulation and pass from the gastrointestinal tract to the bloodstream without being inactivated. Thus, the bioavailability (rate and extent) depends on the sensitivity of the anticancer drug to the conditions of the gastrointestinal tract and its ability to pass from the tract into the bloodstream. Recently, particular attention was attached to quality of life during the therapy. It became of particular importance to enable patients to have a more comfortable life. Moreover, major developments in the diagnostic of cancer increased the number of patients with a cancer at a treatable stage. In this context, oral chemotherapy seems better suited because it enables the patient to lead a normal life, who will spend less time in the hospital and more at home. Before reaching the development stage of new anticancer formulations, different areas of great concern should be taken in consideration. First, it is necessary to consider the toxicity aspects. Chemotherapy is well known to cause several side effects. Particularly, the contact of high concentrations of orally administered cytotoxic agent close to the intestinal wall could cause damage to the intestinal cells and impair the physiological functions of these tissues. Secondly, the patient adherence and economic issues have an important role in the development of a new medicament. Adherence is defined by the International Society for Pharmacoeconomics and Outcome Research (ISPOR), as ‘the degree or extent of conformity to the recommendations about day-to-day treatment by the provider with respect to the timing, dosage and frequency’. Overall adherence was calculated as the number of total administered doses times 100 divided by the total number of scheduled doses. Similarly, mean daily adherence was calculated by considering the number of daily administered doses times 100 divided by the total number of daily scheduled doses. Adherence is a synonymous of

www.drugdiscoverytoday.com Please cite this article in press as: S.. Mazzaferro, et al., Oral delivery of anticancer drugs I: general considerations, Drug Discov Today (2012), http://dx.doi.org/10.1016/ j.drudis.2012.08.004

DRUDIS-1084; No of Pages 10 Drug Discovery Today  Volume 00, Number 00  September 2012

REVIEWS

TABLE 1

Drug

Trade name W

Form

Indication

Altretamine

Hexalen

Capsules

Ovarian cancer

Bexarotene

TargretinW

Capsules

Cutaneous T cell lymphoma

W

Busulfan

Myleran

Coated tablets

Chronic myeloid leukemia

Capecitabine

XelodaW

Coated tablets

Metastatic Breast and Colorectal and Stage III (Dukes’ C) colon

Chlorambucil

ChloraminopheneW

Capsules

Chronic lymphocytic leukemia, malignant lymphomas and Waldensto¨m’s disease

Cyclophosphamide

EndoxanW

Coated tablets

Different cancer diseases (breast, ovarian cancer and leukemia)

Erlotinib hydrochloride

TarcevaW

Coated tablets

Non-small cell lung cancer, pancreatic cancer

Estramustine

EstracytW

Capsules

Hormone-resistant prostate cancer

W

Etoposide

Vepesid

Capsules

Lung cancer, leukemia and cancer of the lymph glands

Fludarabine

FludaraW

Coated tablets

Chronic lymphocytic leukemia

Gefitinib

IressaW

Tablets

Non-small lung carcinoma

W

Ibandronic acid

Ibandronic acid Sandroz

Tablets

Breast neoplasm

Idarubicin

ZavedosW

Capsules

Acute myelogenous leukemia

Imatinib

Glivec

Capsules or tablets

Leukemia, gastrointestinal stromal tumor

Lapatinib

TyverbW

Tablets

Breast neoplasm

W

Lenalidomide

Revlimid

Capsules

Multiple myeloma

Lomustine

BelustineW

Capsules

Brain tumors, Hodgkin’s disease and non-Hodgkin’s lymphoma, melanoma, lung and colon cancer

Melphalan

AlkeranW

Coated tablets

Multiple myeloma

Mercaptopurine

PurinetholW

Tablets

Acute lymphoblastic leukemia

W

Methotrexate

Methotrexate bellon

Tablets

Different kinds of cancers

Mitotane

LysodrenW

Capsules

Adrenal carcinoma

Nilotinib

TasignaW

Capsules

Chronic myeloid leukemia

W

W

Procarbazine

Natulan , Matulan

Capsules

Hodgkin’s lymphoma and other malignant lymphomas

Sorafenib tosylate

NexavarW

Coated tablets

Renal cell carcinoma, advanced primary liver cancer

Capsules

Renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor

W

Sunitinib malate

Sutent

Tegafur-uracil

UFTW

Capsules

Metastatic colorectal tumors

Tegafur-gimeracil-oteracil

W

Teysuno

Capsules

Stomach cancer neoplasm

Temozolomide

TemodalW

Capsules

Brain tumors

W

Thioguanine

Lanvis

Tablets

Acute leukemia and chronic granulocytic leukemia

Topotecan

HycamticW

Capsules

Small lung cancer, uterin, cervical and ovarian neoplasm

Toremifene

FarestonW

Tablets

Breast neoplasm

W

Tretinoin

Vesanoid

Capsules

Acute promyelocytic leukemia

Vinorelbin

NavelbineW

Capsules

Non-small cell lung cancer

compliance, but often preferred because it is generally believed to have a less pejorative and less judgmental connotation [49]. Providing patients with a good educational background on when and how to take their medications [35], and to find new techniques for measuring adherence and persistence are of paramount importance.

Patient’s adherence to treatment An important milestone in oral chemotherapy began in April 1998 with the capecitabine FDA approval [50]. Since then, oral delivery has become more and more an attractive alternative

to i.v. therapy owing to its convenience and ease of administration [36]. Different studies compared patient preference for oral versus i.v. treatment, and in the most part of them the result showed a preference for the oral treatment [51,52]. The main reason reported is the improvement of the patient’s quality of life. The medication can be taken at home. It interferes less with the daily activity than the i.v. treatment [30]. Although patients seem enthusiastic for the oral chemotherapy, this kind of therapy raises a great problem related to the patient’s adherence, especially in chronic conditions such as cancer [53]. Adherence is often referred to as compliance and the editors of

www.drugdiscoverytoday.com 3 Please cite this article in press as: S.. Mazzaferro, et al., Oral delivery of anticancer drugs I: general considerations, Drug Discov Today (2012), http://dx.doi.org/10.1016/ j.drudis.2012.08.004

Reviews  KEYNOTE REVIEW

Some examples of approved oral chemotherapy drugs.

DRUDIS-1084; No of Pages 10 REVIEWS

Drug Discovery Today  Volume 00, Number 00  September 2012

TABLE 2

Some examples of oral cytotoxic drugs in development. Agent

New strategies

Comments

Ref

Paclitaxel (Ptx)

Ptx/cyclosporine A

P-gp inhibitor; similar bioavailability with daily dosing schedule P-gp inhibitor; bioavailability 40% Bioavailability 80%

[37]

Ptx/GF120918 Ptx-HP-b-CD-nanoparticles Reviews  KEYNOTE REVIEW

Docetaxel (Dtx)

Dtx/ritonavir

[38] [39,40]

Dtx/cyclosporine A Dtx/PLA-TPGS/MMT NPs ModraDoc001

CYP450 inhibitor; increment of systemic exposure by 50-fold P-gp inhibitor; increment of bioavailability Bioavailability 78% Oral solid dispersion formulation

[42] [43] [44]

Topotecan

Standard HycamtinW for i.v.

Less toxicity

[45]

Irinotecan

Lipid nanocapsules loaded SN38

Permeability improvement across Caco-2 cells

[46]

Satraplatin

JM216 (prodrug)

Milder toxicity; lack of cross resistance with cisplatin; same efficiency of other platinum drugs

[47]

5-Fluorouracil

Capacitabine (prodrug) ftorafur-uracil (prodrug) S-1 (prodrug)

Promising in colorectal and metastatic breast cancer Good response rate in colorectal and gastric cancer

[48]

‘Compliance in Health Care’ defined it as the extent to which a patient’s behavior (in terms of taking medications, following diets or executing lifestyle changes) coincides with medical care or health advice [54]. A patient is adherent when no dose is missed, no extra dose is taken, and no dose is taken in the wrong quantity or at the wrong time [49]. In the case of i.v. chemotherapy, the patient is in the clinic or hospital and the treatment is provided directly by a health care provider. With the oral chemotherapy, adherence and the measure of adherence becomes more complicated [35]. With parenteral therapy the physician knows exactly the dose and the period to deliver the drug. This level of control is not possible with oral chemotherapy. Many of the responsibilities of managing the regimen and monitoring of doses and toxicity shift from the oncologists to the patient [55]. The patient becomes the real actor of the therapy. He/she must promptly initiate the therapy at the correct time of the day, at the correct dosage and he/she must alert the clinician of adverse symptoms in a timely manner. Adherence can become a challenging task for many patients. For this reason, the decision to take oral chemotherapy must be based on a collaborative discussion between the patient and the physician, with appropriate support from oncology staff [56]. The majority of oncologists consider the oral chemotherapy being advantageous, but not all the patients are good candidates for oral treatment. Usually, the oncologists use their own criteria to select patients, depending on age, previous experiences and side effects related to the treatment. They take into consideration the patient’s wishes to have this kind of treatment and also the presence of a social network for special patients (old patients and children). The relationship between the oncologist and the patient, the organization of consultations and how to consider risk are changed. Oncologists should communicate information to their patients, verify that they understand and make their patients want to adhere to their treatment [57]. Generally, adherence to chronic medication therapy in adult ambulatory care is fair to poor. Approximately 50% of patients will discontinue taking the medication within six months [50]. The main reasons of non-adherence include misinterpretation of 4

[41]

physician instructions, denial, forgetfulness or confusion, dosing frequency and side effects [57–60]. Particularly, children and adolescent adherence is a complex issue. Cameron Tebby in his review [53] discussed different factors involved in the non-adherence of pediatric patients. These factors are human errors, complexity of regimen, duration of therapy, side effects, interaction between the provider and the patient and several factors about the family, such as demographic, psychological, cognitive, social or situational [53,61]. In the same way, non-adherence is a real problem in the elderly population. ‘Polypharmacy’ (i.e. a long medication list) is common in older adults and can predispose to non-adherence [55]. Suboptimal adherence to oral therapy can have severe consequences: it can impede the efficacy of the oral regimens and it can increase the toxicity of the drug, resulting in more costs because of more physician visits, higher hospitalization rates and longer stays [49,62]. For these reasons, great attention was paid to find effective methods to measure patient’s adherence. There are different methods for monitoring adherence and they are divided in two categories: direct and indirect methods. The ‘direct methods’ include the direct observation of the therapy and the measurement of the pharmacokinetic parameters. These methods are easy with the parenteral administration in clinic, but more difficult when the oral chemotherapy is taken at home. Drug or metabolite levels in serum or urine may provide an objective measure of adherence, but such level may vary widely because of pharmacokinetic variations for oral chemotherapy. Moreover, non-adherent patients can manipulate the results by becoming adherent immediately before the physician visit. Among the ‘indirect methods’, we can find (i) patient selfreport: this is the more traditional method, but frequently inaccurate because of poor patient memory or reluctance to report non-adherence; (ii) pill counts and microelectronic monitoring system (MEMS). These latter devices are able to record each time they are opened. The data are collected and processed by a computer to generate a graphic representation of the number of doses taken daily, the number of missed or extra doses and the dosing intervals. The main problem with MEMS is that there is no proof

www.drugdiscoverytoday.com Please cite this article in press as: S.. Mazzaferro, et al., Oral delivery of anticancer drugs I: general considerations, Drug Discov Today (2012), http://dx.doi.org/10.1016/ j.drudis.2012.08.004

DRUDIS-1084; No of Pages 10 Drug Discovery Today  Volume 00, Number 00  September 2012

and follow-up for patients receiving oral chemotherapy within the UK [69].

Economic issues Pharmaco-economic analyses were carried out in clinical trials to evaluate the cost effectiveness of new oral drugs and to make comparison with the cost of infusion administration. To date, pharmaco-economic analyses were carried out for different anticancer drugs including capecitabine [72], capecitabine/cisplatin [56], ibandronate [73,74] and uracil-ftorafur (UFT) [75]. Lokich et al. in 1996 [70] studied the comparison of costs for infusion versus bolus administration for different anticancer drugs, in different tumors and chemotherapy regimens. The model developed for the study identified six cost centers: physician visit costs, clinic visit costs, laboratory costs, drug costs, disposable costs and durable medical equipment (DME) costs. Data analysis showed that the major differences in costs were related to the drug dosage and the toxicity profile. The results showed that the costs for both therapies were similar. In a second work [71] the authors analyzed the charges and the reimbursement for both (oral and i.v.) chemotherapy regimens. Even in this case data did not show substantial differences between the two therapies. There were two limitations to this study analysis: (i) the study was retrospective and conclusions would be more substantive if it were performed prospectively; (ii) the number of the cycles analyzed for each treatment was too small and excluded toxicity-induced, radiology cost and hospitalization. The authors suggested to be careful when analyzing the real cost of chemotherapy and the future studies should include a sufficient number of cycles such as hospitalization and diagnostic studies. In the UK, Cassidy et al. [72] conducted a study in which the oral capecitabine was compared with i.v. 5-fluorouracil/leucovorin (5-FU/LV). For the total cost of the therapy, they took in consideration the direct medical costs to the NHS including:  cost of chemotherapy drugs;  cost of visits for drug administration;  cost of hospital use;  cost of physician consultations for adverse events and for treating them; and  cost of ambulance trips. When the ‘societal costs’ were added, the total costs were approximately £3500 for the oral capecitabine versus £8500 of 5-FU/LV. For this reason, from an economical point of view, they termed capecitabine as a ‘dominant’ treatment strategy. The cost saving was over £5000 per patient. The same study was carried out in the US considering similar parameters, and the results showed that the life-time cost saving with capecitabine versus 5-FU/LV was $1935 per patient [76]. Other studies confirmed these results and supported the benefit of the development of oral chemotherapy. In Spain, an economical assessment compared the costs of the association of oral cisplatin/capecitabine and i.v. cisplatin/fluorouracil in patients with gastric cancer. The annual drug costs per person of the cisplatin/capecitabine regimen were estimated to s1333 higher than cisplatin/fluorouracil. However, if considering the drug administration and adverse event costs, the estimated annual costs reached s2688 per person in the cisplatin/capecitabine versus s4014 of cisplatin/fluorouracil treatment [56].

www.drugdiscoverytoday.com 5 Please cite this article in press as: S.. Mazzaferro, et al., Oral delivery of anticancer drugs I: general considerations, Drug Discov Today (2012), http://dx.doi.org/10.1016/ j.drudis.2012.08.004

Reviews  KEYNOTE REVIEW

that the tablet is really taken as the act of opening a pill counter does not necessary mean that the patient ingested the pill. Furthermore, they are too expensive for an applicability to large scale use [60,63,64]. Whatever the technique used to assess adherence, physicians must realize that the lack of adherence typically reflects the complexity of the regimen rather than willful or manipulative behavior from the patients [50]. In this context, the strategies for promoting appropriate treatment compliance are to educate the patient, to stimulate an individual patient’s motivation to follow instructions and his/ her perception of the risks and benefits. Albrecht and Hoogstraten [65] underlined in their work that compliance is often linked with satisfaction of therapy, in terms of information and communication, understanding acceptance and perceived technical competence. Simons et al. in a recent work [66] investigated the effect of an intensified multidisciplinary pharmaceutical care program on the adherence of patients treated with capecitabine. The study was carried out by dividing patients into two groups (control group and intervention group). The group of patients enrolled in the pharmaceutical care program showed an increased mean overall adherence of 97.9%. However, this increased mean overall adherence was not significantly different from the control group (90.5%). Nevertheless, mean daily adherence was significantly higher in the intervention group (96.8%) than the control group (87.2%). Moreover, variability of both adherence parameters was reduced when pharmaceutical care was provided and at the end of the study, the probability of still being treated with capecitabine was 83% in the intervention group against 48% in the control group. The patients and the family, in case of children or adolescents, become the real actors of the therapy and their education represents a mandatory factor to ensure the success of the therapy [60]. In this context, each protagonist namely physicians, nurses, pharmacists, oncologists have an important role to play. There are different ways to educate the patient, from the print material, individual or group sessions, to video or audiotapes and computer-assisted instruction (CAI). Moore [60] discussed the advantages and disadvantages of each method. She underlined that most patients get benefit by imagining themselves as partners in a therapeutic process, understanding how the medication works, how it should be taken and how to manage the side effects. In this context, the role of oncology nurses becomes really important because they are in charge of the educational programs. It is essential that the nurses know the patient and they let be known, establishing a real relationship with the patients based on trust. They have to stimulate a genuine dialog with patients, listening and accommodating the individual needs and circumstances, emphasizing the patient’s personal choices, setting goals and focusing on the patient’s perspectives. In this way, they would be able to provide patients with the tools they need to adhere to treatment [67,68]. In past few years in the UK, the National Health Service (NHS) has embraced home delivery and home nursing, and has developed strong, mutually beneficial relationships with the independent providers of home healthcare services. The UK Oncology Nursing Society (UKONS) has identified the skills necessary to enhance patient safety. Several private sector healthcare companies have established services, which offer support, monitoring

REVIEWS

DRUDIS-1084; No of Pages 10 REVIEWS

In addition, in some countries such as the UK, a tax (the Value Added Tax, VAT, 17.5%) is applied for the drugs that are purchased by hospitals. On the contrary, when the drugs are prescribed and dispensed to an individual within the community setting they are exempt of VAT. This provides significant benefits to both patients and commissioners of homecare services in terms of greater convenience, reduces drug costs and pharmacy waiting times [69]. Reviews  KEYNOTE REVIEW

Specific features of anticancer drugs to be considered for oral delivery Besides the challenges mentioned above concerning oral delivery of anticancer drugs, further aspects should be considered such as: therapeutic index, dose adjustment considerations, pharmacokinetics, inter and intra-individual variability, and importantly, its potential local toxicity. Individuals have a highly variable capacity to metabolize and eliminate drugs, resulting from a combination of physiological variables, intrinsic (genetic) characteristics and environmental factors that determine each patient’s phenotype. Particularly, many anticancer drugs are characterized by unique and peculiar pharmacokinetic and pharmacodynamic profiles and also by a narrow therapeutic window. Thus, a small variation in the administered dose can lead to severe and life-threatening toxicity in some individuals, and poor antitumor effects in others. Indeed, i.v. formulations enable a precise scheduling of the dose delivered to the patient. During the past 40 years, body surface area (BSA) has certainly made a considerable contribution to doseadaptation, and it can still be correctly employed for a limited number of anticancer agents. Other measures seem to be more appropriate for some agents, including pharmacokinetic monitoring for methotrexate and enzyme phenotyping strategies for agents such as docetaxel. For the long list of anticancer agents where BSA-based dosing does not seem to be accurate, it is suggested that flat-fixed dosing strategies should be implemented and the routine use of normalizing the dose to BSA should be abandoned [77]. In the case of oral delivery, the possibility for dose adaptation should be considered, which can be obtained by adequate formulation. Considerations about dosing strategies and inter- to intra-individual variability related to the toxicity aspects are of particular importance. The side effects of chemotherapy can be so severe, they can escalate beyond what is tolerable or safe for the patient and therapy may be suspended until the side effects are controlled. This period called ‘therapy holiday’ is not recommended because of lost treatment benefits on cancer and resulting disease progression [78]. The most part of cytotoxic agents used in therapy are well known to be emetic. After i.v. administration, the side effects include nausea, vomiting and diarrhea. The cause of these side effects is probably linked to a specific action of cytotoxic agents against rapidly proliferating cells of the gastrointestinal tract [79]. The question now is: ‘will this gastrointestinal toxicities increase with the oral administration?’ The answer to this question is not easy and universal. Each anticancer agent has its own toxicity profile depending on its mechanism of action, the therapeutic regimen, duration of treatment and dose schedule. The intraperitoneal administration of 5-FU induces apoptosis or cell cycle arrest in intestinal cells. In the same way, the administration of methotrexate induces focal vacuolization and ultra-structural damage of the immature intestinal crypt cells. These damages 6

Drug Discovery Today  Volume 00, Number 00  September 2012

lead to morphological changes associated with a reduction of the intestinal mucosal mass, mucosal protein and DNA content, body weight loss and a significant increase in intestinal transit time and permeability. This enterotoxicity can be reduced with the oral co-administration of glutamine [80,81]. Numerous clinical trials have associated the administration of glutamine with radiation and chemotherapy with promising results [80]. Other common side effects related to chemotherapy are stomatitis and difficulty in swallowing. Even in this case, the administration of low oral doses of glutamine after chemotherapy led to a reduction of the duration and the severity of mouth pain [79]. Oral mucositis represents a major non-hematologic complication in cytotoxic chemotherapy leading to pain, odynophagie, dysgeusia, and subsequent dehydration and malnutrition, thus reducing the patient’s quality of life [82]. Comparing different clinical studies of oral versus i.v. administration of different kinds of anticancer drugs, such as vinorelbine, topotecan, etoposide, we can summarize that the hematological toxicities, neutropenia and/or leucopenia were the principal side effects in both treatments. Among the non-hematological side effects, gastrointestinal toxicities (i.e. nausea, diarrhea and vomiting) were the predominant adverse effects and they were only slightly higher after oral than i.v. administration [45,52,83–85]. However, a lower incidence of these side effects was reported after oral administration of capecitabine and UFT versus i.v. administration of 5-FU and leucovorin for the treatment of colorectal cancer [52,86]. Particular attention concerning toxicity considerations is required when the oral chemotherapy is concomitant to the delivery (whatever the route) of ATP-binding cassette (ABC) transporters (or efflux pumps) or cytochrome P450 (CYP450) blockers. The resulting inhibition presents two sides of the coin. It can lead to an important enhancement of the plasma concentration of the cytotoxic agent with a resulting improvement of the bioavailability of drug, by contrast, it can lead to an enhancement of toxicity. The efflux pumps are expressed in different kinds of normal cells, but particularly, three tissues need closer examination: hematological stem cells, gut and endothelial cells in the blood–brain barrier. The administration of a (P-gp inhibitor can result in an exacerbation of neutropenia, incidence of intestinal mucositis and an increased amount of anticancer drug in the central nervous system. The same considerations hold good for the inhibition of CYP450 [87]. Van Waterschoot et al. [88] studied the toxicity of the oral administration of docetaxel in mice lacking all CYP3A and P-gp genes (Cyp3a/Mdr1a / ), in comparison with wild-type mice. In these deficient conditions mice deteriorated quickly and they died in four days. The most significant cause was the degeneration and necrosis of the intestinal mucosa throughout the entire intestinal tract. For these reasons, the association must be carefully studied; ideally, the blockage must be specific and the duration needs to be long enough to allow efficacy, but short enough to limit toxicity [87]. Different clinical studies showed promising results, and the toxicity observed following oral anticancer drug administration in combination with different kinds of blockers, were mild or slightly more frequently than the i.v. treatment [42,89–91]. Some drug delivery systems may reduce the toxicity of the anticancer agents. For example, special formulations might be

www.drugdiscoverytoday.com Please cite this article in press as: S.. Mazzaferro, et al., Oral delivery of anticancer drugs I: general considerations, Drug Discov Today (2012), http://dx.doi.org/10.1016/ j.drudis.2012.08.004

DRUDIS-1084; No of Pages 10 Drug Discovery Today  Volume 00, Number 00  September 2012

Oral delivery of anticancer drugs is often faced with identified formulation issues Inadequate aqueous solubility From a physico-chemical point of view, major anticancer drugs are sparingly water-soluble, making it difficult to formulate them efficiently. Improving the apparent solubility of such substances might only solve one aspect of the problem but it is a starting point to design efficient pharmaceutical formulations. In this context, different strategies were used to improve anticancer drug solubility by using pharmaceutical excipients, drug delivery systems or chemical reactions to form prodrugs. Concerning pharmaceutical excipients used for the solubilization of anticancer drugs, water miscible co-solvents, such as ethanol, methanol, methylene chloride or acetonitrile, 14 mM in isopropanol [96] and water-insoluble organic solvents, such as oils, triglycerides, vitamin E, or their associations are generally used. Furthermore, micelles, liposomes, micro and nanocapsules, dendrimers, emulsions, microemulsions and nano-emulsions were largely used to increase apparent water solubility of anticancer drugs [97–99]. One strategy to improve anticancer drug aqueous apparent solubility is to use cyclodextrins, which are macromolecules composed of cyclic oligosaccharides of D-(+)glucopyranose units, all in chair conformation, linked by a-(1,4)-glucosidic bonds. Complexation of poorly water-soluble drugs with natural or chemically modified cyclodextrins represents an interesting strategy for increasing their apparent water solubility [100–104] and offers further possibilities for their pharmaceutical formulation ranging from conventional to colloidal dispersions [39,105–107], for review see [105,108–110]. Interactions generally occur between cyclodextrins and lipophilic molecules or lipophilic groups on the guest molecules resulting in the formation of drug and/or cyclodextrin complexes [105–107,111]. These complexes can be much more water-soluble than the lipophilic molecule [112]. So far, cyclodextrins were used to increase the solubility of the poorly water-soluble drugs to increase their bioavailability. However, the hydrophilic external surface can represent a drawback, because it can result in a lack of affinity for the biological barriers [113]. In this context, researchers focused their interest in the cyclodextrin derivatives and in particular in the advantages of the cyclodextrins encapsulated into colloidal carriers. Ducheˆne et al. [102] showed the increase of loading capacity of poly(isobutyl cyanoacrylate) nanospheres by employing hydroxypropylb-cyclodextrin (HP-b-CD) and the possibility of the spontaneous

formation of either nanocapsules or nanospheres by nanoprecipitation of amphiphilic cyclodextrin diesters. In the recent years, the use of cyclodextrins has been successfully applied to increase the encapsulation of different lipophilic drugs [114], such as benzophenone, tamoxifen, paclitaxel [105,115] and saquinavir [116].

Intestinal transit After its oral administration, the active drug has to reach the intestinal absorption site. So far, multiparticulate drug delivery systems (DDS), including micro and nanoparticulate systems, were employed to improve the intestinal absorption of hydrophilic [117,118] or hydrophobic drugs [39,40]. In this context, the use of different kinds of polymers such as polysaccharides (chitosan or dextran), acrylic copolymers (Eudragit), phospholipids or cellulosic derivatives [cellulose acetate phthalate CAT or cellulose acetate trimellitate CAP and hydroxypropyl methylcellulose phthalate (HPMCP)], confer to these particulate systems adequate gastroresistant properties [119,120]. If they pass intact through the stomach they can reach the small intestine where these DDS should release their drug content. For some drugs, the transit time through the intestine can be too short leading to incomplete absorption, resulting in low bioavailability and poor efficacy. Because the transit time in the gastrointestinal tract can be inadequate, many researchers have sought to enhance the duration available for absorption by rendering the dosage form mucoadhesive. The phenomenon of mucoadhesion results from the combined effects of different mechanisms depending on the nature of the dosage form as well as the polymers used [121–124]. The use of mucoadhesive DDS can (i) result in increased local drug concentrations, which is favorable to absorption, (ii) improvement of the effectiveness of the drugs by maintaining the plasma drug concentration at the therapeutic levels for prolonged periods of time and (iii) in some cases restricting absorption to a specific site in the intestine [125,126]. Such dosage forms may be beneficial for the oral delivery of anticancer drugs impaired by low intestinal permeabilities.

Drug metabolism and efflux pumps in the intestinal wall The metabolism of anticancer drugs and/or their efflux in the intestinal wall during the absorption process represents another problem arising when an anticancer drug is orally administered. Consequently, cancer cells became resistant to the drugs [127]. It has been demonstrated that the expression and the activity of ABC transporters and the metabolic CYP450 enzyme expressed in the gastrointestinal tract could seriously impair the bioavailability of anticancer drugs [128–130]. Physiologically, ABC transporters have an important role in body defense; they are recognized for their ability to modulate the normal absorption, distribution, metabolism, excretion and toxicity of xenobiotics [131–133]. In this situation, an important strategy to achieve an efficient oral chemotherapy may exist in the concomitant delivery of inhibitors of the ABC transporters and CYP450 with the aim of increasing the drug bioavailability [88,134]. However, the inhibition of the metabolism mechanisms may simultaneously influence the distribution and the bioavailability of other xenobiotics, leading to unwanted side effects.

www.drugdiscoverytoday.com 7 Please cite this article in press as: S.. Mazzaferro, et al., Oral delivery of anticancer drugs I: general considerations, Drug Discov Today (2012), http://dx.doi.org/10.1016/ j.drudis.2012.08.004

Reviews  KEYNOTE REVIEW

able to protect the gastrointestinal tract against ulceration and mucositis. This was proved for the oral administration of indomethacin, a non-steroidal anti-inflammatory drug, which use is associated with ulcer-necrotic effects on the gastrointestinal mucosa. Encapsulation of the drug into nanocapsules enabled therapeutic activity with limited side effects [92–94]. Local and systemic adverse effects because of high concentrations of drug can be minimized by the use of controlled release delivery systems [95]. In terms of formulation strategy, it could be interesting to formulate the inhibitors of the efflux pumps and the cytochrome to control their release and their site of action. In the specific case of oral administration, it can be useful to use mucoadhesive carriers to limit the inhibition effects in restricted areas of the gastrointestinal tract.

REVIEWS

DRUDIS-1084; No of Pages 10 REVIEWS

Concluding remarks

Reviews  KEYNOTE REVIEW

Oral chemotherapy appears to be promising to developments in the future of oncology. Different fields of science are working to improve oral delivery of anticancer drugs. Many problems must to be solved. The achievement of suitable pharmacokinetic profiles and the toxicity issues are probably the most important limitations for the oral administration of anticancer drugs. However, these pharmaceutical issues represent only one aspect of oral chemotherapy. Indeed, if there will be new drugs available for the oral chemotherapy, it is worth knowing that the protagonists of therapy should be prepared for this fundamental change. In fact, the role of oncologists, physicians, nurses and in particular patients can be really impacted by a switch from i.v. to oral delivery. Many of the responsibilities in the management of the regimen, monitoring of doses and adverse effects are shifted from the oncologist to patient and the adherence to the therapy

Drug Discovery Today  Volume 00, Number 00  September 2012

might become a great concern. In the case of i.v. chemotherapy, the hospitalization enables the monitoring of the treatment directly by the health care provider, which is not possible with the oral chemotherapy. The patient and the family, for children or adolescents must promptly initiate the therapy at the correct time of the day, at the correct dosage and alert the clinician of adverse symptoms in a timely manner. For this reason, education of patients, stimulating an individual patient’s motivation to follow instructions and his/her perception of the risks and benefits will represent a new task for oncology nurses and oncologists.

Acknowledgement The Association of Cancer Research ‘ARC’ is gratefully acknowledged for the financial support which enabled Ms Silvia Mazzaferro to conduct this study.

References 1 Fitch, K. et al. (2010) Parity for oral and intravenous injected cancer drugs. Milliman Rep. 1–20 2 Roos, W.P. and Kaina, B. (2006) DNA damage-induced cell death by apoptosis. Trends Mol. Med. 12, 440–450 3 Helleday, T. et al. (2008) DNA repair pathways as targets for cancer therapy. Nat. Rev. 8, 193–204 4 Kaye, S. (1998) New antimetabolites in cancer chemotherapy and their clinical impact. Br. J. Cancer 78, 1–7 5 da Rocha, A.B. et al. (2001) Natural products in anticancer therapy. Curr. Opin. Pharmacol. 1, 364–369 6 Johnson, I. et al. (1963) The vinca alkaloids: a new class of oncolytic agents. Cancer Res. 2, 1390–1427 7 Kavallaris, M. et al. (2001) Multiple microtubule alterations are associated with vinca alkaloid resistance in human leukemia cells. Cancer Res. 61, 5803–5809 8 Schrama, D. et al. (2006) Antibody targeted drugs as cancer therapeutics. Nat. Rev. Drug Discov. 5, 147–159 9 Reichert, J.M. and Valge-Archer, V.E. (2007) Development trends for monoclonal antibody cancer therapeutics. Nat. Rev. Drug Discov. 6, 349–356 10 Adams, G.P. and Weiner, L.M. (2005) Monoclonal antibody therapy of cancer. Nat. Biotechnol. 23, 1147–1157 11 Mendelsohn, J. (2001) The epidermal growth factor receptor as a target for cancer therapy. Endocr. Relat. Cancer 8, 3–9 12 Allegra, C. et al. (2009) American Society of Clinical Oncology Provisional Clinical Opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J. Clin. Oncol. 12, 2091–2096 13 Gilboa, E. (2007) DC-based cancer vaccines. J. Clin. Invest. 117, 1195–1203 14 Greten, T.F. et al. (1999) Cancer vaccines. J. Clin. Oncol. 17, 1047–1060 15 Schlom, J. et al. (2007) Cancer vaccines: moving beyond current paradigms. Clin. Cancer Res. 17, 3884–3891 16 Srivastava, P.K. (2006) Therapeutic cancer vaccines. Curr. Opin. Immunol. 18, 201–205 17 Fisher, B. et al. (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl. Cancer Inst. 90, 1371–1388 18 Osborne, C. (1998) Tamoxifen in the treatment of breast cancer. N. Engl. J. Med. 339, 1609–1618 19 Brueggemeier, R. et al. (2005) Aromatase inhibitors in the treatment of breast cancer. Endocr. Rev. 26, 331–345 20 Ellis, G. et al. (2008) Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J. Clin. Oncol. 26, 4875–4882 21 Smith, I. and Dowsett, M. (2003) Aromatase inhibitors in breast cancer. N. Engl. J. Med. 348, 2431–2442 22 Terwogt, J.M.M. et al. (1999) Clinical pharmacology of anticancer agents in relation to formulations and administration routes. Cancer Treat. Rev. 25, 83–101 23 Kruijtzer, C. et al. (2002) Improvement of oral drug treatment by temporary inhibition of drug transporters and/or cytochrome P450 in the gastrointestinal tract and liver: an overview. Oncologist 7, 516–630

8

24 Weinberger, S. and Martinez, J. (1988) Characterization of hydrolysis of [leu]enkephalin and D-ala2-[L-leu] enkephalin in rat plasma. J. Pharmacol. Exp. Ther. 247, 129–135 25 Wheate, N.J. et al. (2010) The status of platinum anticancer drugs in the clinic and in clinical trials. Dalton. Trans. 39, 8113–8127 26 Singla, A.K. et al. (2002) Paclitaxel and its formulations. Int. J. Pharm. 235, 179–192 27 Van Tellingen, O. et al. (1999) Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients. Br. J. Cancer 81, 330–335 28 Gelderblom, H. et al. (2002) Influence of Cremophor El on the bioavailability of intraperitoneal paclitaxel. Clin. Cancer Res. 8, 1237–1241 29 Baker, S.D. et al. (2004) Simultaneous analysis of docetaxel and the formulation vehicle polysorbate 80 in human plasma by liquid chromatography/tandem mass spectrometry. Anal. Biochem. 324, 276–284 30 Borner, M. and et al. Answering patients’ needs: oral alternatives to intravenous therapy, (2001) Oncologist 6 (Suppl. 4) 12–16 31 Payne, S.A. (1992) A study of life in cancer patients receiving palliative chemotherapy. Soc. Sci. Med. 35, 1505–1509 32 Batlle, J.F. et al. (2004) Oral chemotherapy: potential benefits and limitations. Clin. Transl. Oncol. 6, 335–340 33 Catania, C. et al. (2005) 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. 92, 265–272 34 Fallowfield, L. (2005) Patients’ preference for administration of endocrine treatments by injection or tablets: results from a study of women with breast cancer. Ann. Oncol. 17, 205–210 35 Halfdanarson, T.R. and Jatoi, A. (2010) Oral cancer chemotherapy: the critical interplay between patient education and patient safety. Curr. Oncol. Rep. 12, 247–252 36 O’neill, V.J. and Twelves, C.J. (2002) Oral cancer treatment: developments in chemotherapy and beyond. Br. J. Cancer 87, 933–937 37 Britten, C.D. et al. (2000) Oral paclitaxel and concurrent cyclosporin A: targeting clinically relevant systemic exposure to paclitaxel. Clin. Cancer Res. 6, 3459–3468 38 Bardelmeijer, H.A. et al. (2000) Increased oral bioavailability of paclitaxel by GF120918 in mice through selective modulation of P-glycoprotein. Clin. Cancer Res. 6, 4416–4421 ¨ eros, M. et al. (2009) Combined hydroxypropyl-[beta]-cyclodextrin and poly 39 Agu (anhydride) nanoparticles improve the oral permeability of paclitaxel. Eur. J. Pharm. Sci. 38, 405–413 ¨ eros, M. et al. (2010) Increased oral bioavailability of paclitaxel by its 40 Agu encapsulation through complex formation with cyclodextrins in poly(anhydride) nanoparticles. J. Control. Release 145, 2–8 41 Bardelmeijer, H.A. et al. (2002) Low systemic exposure of oral docetaxel in mice resulting from extensive first-pass metabolism is boosted by ritonavir. Cancer Res. 62, 6158–6164 42 Malingre´, M.M. et al. (2001) Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J. Clin. Oncol. 19, 1160–1166

www.drugdiscoverytoday.com Please cite this article in press as: S.. Mazzaferro, et al., Oral delivery of anticancer drugs I: general considerations, Drug Discov Today (2012), http://dx.doi.org/10.1016/ j.drudis.2012.08.004

DRUDIS-1084; No of Pages 10

43 Feng, S.S. et al. (2009) Poly(lactide)-vitamin E derivative/montmorillonite nanoparticle formulations for the oral delivery of Docetaxel. Biomaterials 30, 3297–3306 44 Moes, J.J. et al. (2011) Pharmaceutical development and preliminary clinical testing of an oral solid dispersion formulation of docetaxel (ModraDoc001). Int. J. Pharm. 420, 244–250 45 Gore, M. et al. (2002) A randomised trial of oral versus intravenous topotecan in patients with relapsed epithelial ovarian cancer. Eur. J. Cancer 38, 57–63 46 Roger, E. et al. (2011) Development and characterization of a novel lipid nanocapsule formulation of Sn38 for oral administration. Eur. J. Pharm. Biopharm. 79, 181–188 47 Choy, H. et al. (2008) Current status and future prospects for satraplatin, an oral platinum analogue. Clin. Cancer Res. 14, 1633–1638 48 Malet-Martino, M. and Martino, R. (2002) Clinical studies of three oral prodrugs of 5-fluorouracil (capecitabine, UFT, S-1): a review. Oncologist 7, 288–323 49 Ruddy, K. et al. (2009) Patient adherence and persistence with oral anticancer treatment. CA. Cancer J. Clin. 59, 56–66 50 Weingart, S. et al. (2008) NCCN task force report: oral chemotherapy. J. Natl. Compr. Cancer Netw. 6, S-1–S-16 51 Liu, G. et al. (1997) Patient preferences for oral versus intravenous palliative chemotherapy. J. Clin. Oncol. 15, 110–115 52 Borner, M. et al. (2002) Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur. J. Cancer 38, 349–358 53 Tebbi, C. (1993) Treatment compliance in childhood and adolescence. Cancer 71, 3441–3449 54 Haynes, R.B. et al. (1979) Compliance in health care. Can. Med. Assoc. J. 3441–3449 55 Lichtman, S.M. and Boparai, M.K. (2008) Anticancer drug therapy in the older cancer patient: pharmacology and polypharmacy. Curr. Treat. Options Oncol. 71, 191–203 56 Irshad, S. and Maisey, N. (2010) Considerations when choosing oral chemotherapy: identifying and responding to patient need. Eur. J. Cancer Care 19, 5–11 57 Denois, V. et al. (2010) Adherence with oral chemotherapy: results from a qualitative study of the behaviour and representations of patients and oncologists. Eur. J. Cancer Care 1–8 58 Hulka, B. et al. (1976) Communication, compliance, and concordance between physicians and patients with prescribed medications. Am. J. Public Health 66, 847–853 59 Kruse, W. et al. (1991) Dosage frequency and drug-compliance behaviour – a comparative study on compliance with a medication to be taken twice or four times daily. Eur. J. Clin. Pharmacol. 41, 589–592 60 Moore, S. (2007) Facilitating oral chemotherapy treatment and compliance through patient/family-focused education. Cancer Nurs. 30, 112–122 61 Griffith, S. (1990) A review of the factors associated with patient compliance and the taking of prescribed medicines. Br. J. Gen. Pract. 40, 114–116 62 Partridge, A. et al. (2009) Adherence to oral cancer therapies: challenges and opportunities. Am. Soc. Clin. Oncol. 124–128 63 Partridge, A.H. et al. (2002) Adherence to therapy with oral antineoplastic agents. J. Natl. Cancer Inst. 94, 652–661 64 Patton, J. (2008) Increased use of oral chemotherapy drugs spurs increased attention to patient compliance. J. Oncol. Pharm. Pract. 4, 175–177 65 Albrecht, G. and Hoogstraten, J. (1998) Satisfaction as a determinant of compliance. Commun. Dent. Oral. 26, 139–146 66 Simons, S. et al. (2011) Enhancing adherence to capecitabine chemotherapy by means of multidisciplinary pharmaceutical care. Support. Care Cancer 19, 1009–1018 67 Palmieri, F. and Barton, D. (2007) Challenges of oral medications in patients with advanced breast cancer. Semin. Oncol. Nurs. 23, S17–S22 68 McLeod, D. et al. (2010) Knowing the family: interpretations of family nursing in oncology and palliative care. Eur. J. Oncol. Nurs. 14, 29–34 69 Vidall, C. (2010) Providing community oral chemotherapy services. Eur. J. Cancer Care 19, 29–34 70 Lokich, J. et al. (1996) Comparison of costs for infusion versus bolus chemotherapy administration: analysis of five standard chemotherapy regimens in three common tumors. Part one: model projections for cost based on charges. Cancer 78, 294–299 71 Lokich, J. et al. (1996) Comparison of costs for infusion versus bolus chemotherapy administration. Part two: use of charges versus reimbursement for cost basis. Cancer 78, 300–303 72 Cassidy, J. et al. (2006) Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes’ C colon cancer: the X-ACT trial. Br. J. Cancer 94, 1122–1129

REVIEWS

73 De Cock, E. et al. (2005) Cost-effectiveness of oral ibandronate compared with intravenous (i.v.) zoledronic acid or i.v. generic pamidronate in breast cancer patients with metastatic bone disease undergoing i.v. chemotherapy. Support. Care Cancer 13, 975–986 74 De Cock, E. et al. (2005) Cost-effectiveness of oral ibandronate versus IV zoledronic acid or IV pamidronate for bone metastases in patients receiving oral hormonal therapy for breast cancer in the United Kingdom. Clin. Ther. 27, 1295–1310 75 Eng, C. et al. (2001) Oral fluoropyrimidine treatment of colorectal cancer. Clin. Colorectal Cancer 1, 95–103 76 Twelves, C. (2006) Xeloda1 in adjuvant colon cancer therapy (X-ACT) trial: overview of efficacy, safety, and cost-effectiveness. Clin. Colorectal Cancer 6, 276–287 77 Felici, A. et al. (2002) Dosing strategies for anticancer drugs: the good, the bad and body-surface area. Eur. J. Cancer 38, 1677–1684 78 Reese, D. et al. Oral oncology treatment regimens and the role of medication therapy management on patient adherence and compliance. http://www.accccancer.org/publications/pdf/usoncologywhitepaper.pdf 79 Anderson, P. et al. (1998) Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer 83, 1433–1439 80 Bajin-Katic´, K. et al. (2004) Changes of biochemical parameters in rat intestinal mucosa induced by methotrexate and effects of enteral administration of glutamine. Arch. Oncol. 12, 35–38 81 Bajin-Katic´, K. et al. (2006) Intestinal alkaline phosphatase activity as a molecular marker of enterotoxicity induced by single dose of 5-fluorouracil and protective role of orally administered glutamine. Arch. Oncol. 14, 101–105 ¨ stler, W. et al. (2001) Oral mucositis complicating chemotherapy and/or 82 Ko radiotherapy: options for prevention and treatment. CA. Cancer J. Clin. 51, 290–315 83 Girling, D. (1996) Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Lancet 348, 563–566 84 Jassem, J. et al. (2001) A multicenter randomized phase II study of oral vs. intravenous vinorelbine in advanced non-small-cell lung cancer patients. Ann. Oncol. 12, 1375–1378 85 Eckardt, J. et al. (2006) Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer. J. Clin. Oncol. 24, 2044–2051 86 Hoff, P. et al. (2001) Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J. Clin. Oncol. 19, 2282–2292 87 Dantzig, A.H. et al. (2003) Considerations in the design and development of transport inhibitors as adjuncts to drug therapy. Adv. Drug Deliv. Rev. 55, 133–150 88 Van Waterschoot, R.A.B. et al. (2009) Absence of both cytochrome P450 3A and Pglycoprotein dramatically increases docetaxel oral bioavailability and risk of intestinal toxicity. Cancer Res. 69, 8996–9002 89 Meerum Terwogt, J.M. et al. (1999) Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin. Cancer Res. 5, 3379–3384 90 Planting, A.S.T. et al. (2005) A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 55, 91–99 91 Malingre´, M.M. et al. (2001) A phase I and pharmacokinetic study of bi-daily dosing of oral paclitaxel in combination with cyclosporin A. Cancer Chemother. Pharmacol. 47, 347–354 92 Skiba, M. et al. (1995) Evaluation of gastrointestinal behaviour in the rat of amphiphilic [beta]-cyclodextrin nanocapsules, loaded with indomethacin. Int. J. Pharm. 126, 275–279 93 Ammoury, N. et al. (1993) Indomethacin-loaded poly(D,L-lactide) nanocapsules protection from gastrointestinal ulcerations and anti-inflammatory activity evaluation in rats. Clin. Mater. 13, 121–130 94 De Chasteigner, S. et al. (1995) Gastro-intestinal tolerance study of a freeze-dried oral dosage form of indomethacin-loaded nanocapsules. STP Pharma Sci. 5, 242–246 95 Florence, A. and Jani, P. (1994) Novel oral drug formulations. Their potential in modulating adverse effects. Drug Saf. 10, 233–266 96 Adams, J.D. et al. (1993) Taxol: a history of pharmaceutical development and current pharmaceutical concerns. J. Natl. Cancer Inst. 15, 141–147 97 Bromberg, L. (2008) Polymeric micelles in oral chemotherapy. J. Control. Release 128, 99–112 98 Constantinides, P. and Wasan, K.M. (2007) Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs: in vitro/in vivo case studies. J. Pharm. Sci. 96, 235–248

www.drugdiscoverytoday.com 9 Please cite this article in press as: S.. Mazzaferro, et al., Oral delivery of anticancer drugs I: general considerations, Drug Discov Today (2012), http://dx.doi.org/10.1016/ j.drudis.2012.08.004

Reviews  KEYNOTE REVIEW

Drug Discovery Today  Volume 00, Number 00  September 2012

DRUDIS-1084; No of Pages 10 REVIEWS

Reviews  KEYNOTE REVIEW

99 Gao, P. et al. (2003) Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J. Pharm. Sci. 92, 2386–2398 100 Brewster, M.E. and Loftsson, T. (2007) Cyclodextrins as pharmaceutical solubilizers. Adv. Drug Deliv. Rev. 59, 645–666 101 Del Valle, E. (2004) Cyclodextrins and their uses: a review. Process Biochem. 39, 1033–1046 102 Ducheˆne, D. et al. (1999) Cyclodextrins in targeting: application to nanoparticles. Adv. Drug Deliv. Rev. 36, 29–40 103 Loftsson, T. and Ducheˆne, D. (2007) Cyclodextrins and their pharmaceutical applications. Int. J. Pharm. 329, 1–11 104 Rajewski, R.A. and Stella, V.J. (1996) Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery. J. Pharm. Sci. 85, 1142–1169 105 Daoud-Mahammed, S. et al. (2009) Cyclodextrin and polysaccharide-based nanogels: entrapment of two hydrophobic molecules, benzophenone and tamoxifen. Biomacromolecules 10, 547–554 106 Othman, M. et al. (2009) Microcalorimetric investigation on the formation of supramolecular nanoassemblies of associative polymers loaded with gadolinium chelate derivatives. Int. J. Pharm. 379, 218–225 107 Segura-Sanchez, F. et al. (2009) Elucidation of the complexation mechanism between (1)-usnic acid and cyclodextrins studied by isothermal titration calorimetry and phase-solubility diagram experiments. J. Mol. Recognit. 22, 232–241 108 Bellocq, N. et al. (2003) Transferrin-containing, cyclodextrin polymer-based particles for tumor-targeted gene delivery. Bioconjugate Chem. 14, 1122–1123 109 Bouchemal, K. et al. (2009) A comprehensive study on the inclusion mechanism of benzophenone into supramolecular nanoassemblies prepared using two watersoluble associative polymers. J. Therm. Anal. Calorim. 98, 57–64 110 Maestrelli, F. et al. (2010) New ‘drug-in cyclodextrin-in deformable liposome’ formulations to improve the therapeutic efficacy of local anaesthatics. Int. J. Pharm. 395, 222–231 111 Mazzaferro, S. et al. (2011) Bivalent sequential binding of docetaxel to methyl-bcyclodextrin. Int. J. Pharm. 416, 171–180 112 Loftsson, T. et al. (2004) Role of cyclodextrins in improving oral drug delivery. Am. J. Drug Deliv. 2, 261–275 113 Ducheˆne, D. et al. (1999) Cyclodextrins and carrier systems. J. Control. Release 62, 263–268 114 Monza da Silveira, A. et al. (1998) Combined poly(isobutylcyanoacrylate) and cyclodextrins nanoparticles for enhancing the encapsulation of lipophilic drugs. Pharm. Res. 15, 1051–1055 115 Bilensoy, E. et al. (2008) Safety and efficacy of amphiphilic b-cyclodextrin nanoparticles for paclitaxel delivery. Int. J. Pharm. 347, 163–170 116 Boudad, H. et al. (2001) Combined hydroxypropyl-[beta]-cyclodextrin and poly (alkylcyanoacrylate) nanoparticles intended for oral administration of saquinavir. Int. J. Pharm. 218, 113–124

10

Drug Discovery Today  Volume 00, Number 00  September 2012

117 Sajeesh, S. et al. (2010) Surface functionalized polymethacrylic acid based hydrogel microparticles for oral delivery. Eur. J. Pharm. Biopharm. 74, 209–218 118 Sajeesh, S. et al. (2010) Cyclodextrin complexed insulin encapsulated hydrogel microparticles: an oral delivery system for insulin. J. Control. Release 147, 377–384 119 Fonseca, L.S. et al. (2008) Nanocapsule@xerogel microparticles containing sodium diclofenac: a new strategy to control the release of drugs. Int. J. Pharm. 358, 292–295 120 Fricker, G. et al. (2010) Phospholipids and lipid-based formulations in oral drug delivery. Pharm. Res. 27, 1469–1486 121 Mazzaferro, S. et al. (2012) Intestinal permeation enhancement of docetaxel encapsulated into methyl-beta-cyclodextrin/poly(isobutylcyanoacrylate) nanoparticles coated with thiolated chitosan. J. Control. Release 162, 568–574 122 Dodou, D. et al. (2005) Mucoadhesives in the gastrointestinal tract: revisiting the literature for novel applications. Eur. J. Pharm. Biopharm. 60, 1–16 123 Huang, Y. et al. (2000) Molecular aspects of muco-and bioadhesion: tethered structures and site-specific surfaces. J. Control. Release 65, 63–71 124 Petit, B. et al. (2012) The counterbalanced effect of size and surface properties of chitosan-coated poly(isobutylcyanoacrylate) nanoparticle on mucoadhesion due to pluronic F68 addition. Pharm. Res. 29, 943–952 125 Bravo-Osuna, I. et al. (2007) Mucoadhesion mechanism of chitosan and thiolated chitosan-poly(isobutyl cyanoacrylate) core–shell nanoparticles. Biomaterials 28, 2233–2243 126 Ponchel, G. and Irache, J.M. (1998) Specific and non-specific bioadhesive particulate systems for oral delivery to the gastrointestinal tract. Adv. Drug Deliv. Rev. 34, 191–219 127 Gottesman, M.M. (1993) How cancer cells evade chemotherapy: sixteenth Richard and Hinda Rosenthal Foundation award lecture. Cancer Res. 53, 747 128 Oostendorp, R.L. et al. (2009) The biological and clinical role of drug transporters at the intestinal barrier. Cancer Treat. Rev. 35, 137–147 129 Benet, L.Z. et al. (1999) Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. J. Control. Release 62, 25–31 130 Chan, L.M.S. et al. (2004) The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur. J. Pharm. Sci. 21, 25–51 131 Leslie, E.M. et al. (2005) Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol. Appl. Pharmacol. 204, 216–237 132 Schinkel, A.H. and Jonker, J.W. (2003) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv. Drug Deliv. Rev. 55, 3–29 133 Leslie, E. et al. (2001) Toxicological relevance of the multidrug resistance protein 1. MRP1 (ABCC1) and related transporters. Toxicology 167, 3–23 134 Constantinides, P.P. and Wasan, K.M. (2006) Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs: in vitro/in vivo case studies. J. Pharm. Sci. 96, 235–248

www.drugdiscoverytoday.com Please cite this article in press as: S.. Mazzaferro, et al., Oral delivery of anticancer drugs I: general considerations, Drug Discov Today (2012), http://dx.doi.org/10.1016/ j.drudis.2012.08.004