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Impact of pharmacokinetic-pharmacodynamic modelling in early clinical drug development
Accepted Manuscript Impact of pharmacokinetic-pharmacodynamic modelling in early clinical drug development
Jasper Dingemanse, Andreas Krause PII: DOI: Reference:
S0928-0987(17)30270-1 doi: 10.1016/j.ejps.2017.05.042 PHASCI 4056
To appear in:
European Journal of Pharmaceutical Sciences
Received date: Revised date: Accepted date:
19 May 2017 ###REVISEDDATE### 19 May 2017
Please cite this article as: Jasper Dingemanse, Andreas Krause , Impact of pharmacokinetic-pharmacodynamic modelling in early clinical drug development, European Journal of Pharmaceutical Sciences (2017), doi: 10.1016/j.ejps.2017.05.042
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ACCEPTED MANUSCRIPT Impact of pharmacokinetic-pharmacodynamic modelling in early clinical drug development Jasper Dingemanse, PhD, PharmD, FCP, Andreas Krause, PhD Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123
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Allschwil, Switzerland
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Author for correspondence:
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Jasper Dingemanse, PhD, PharmD, FCP, Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland
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Email: [email protected], Tel. +41 61 565 64 63, Fax: +41 61 565 62 00
Abstract
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Early clinical pharmacology studies in healthy subjects are often dissociated from patient studies. In
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this review we encourage the use of modelling and simulation techniques to generate valuable information at an early stage of clinical development. We illustrate these principles by presenting 5
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different case studies from a spectrum of therapeutic drug classes. Their application leads to a better understanding of drug characteristics early on, thereby facilitating the design of dose-finding studies
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in the target patient population and saving resources.
Keywords Clinical pharmacology; drug development; modelling; pharmacokinetics; pharmacodynamics
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ACCEPTED MANUSCRIPT 1. Introduction The science of clinical pharmacology traditionally encompasses the assessment of tolerability, safety, pharmacokinetics (PK), and pharmacodynamics (PD). For most therapeutic areas and drug classes this information is obtained by the conduct of single- and multiple-ascending dose studies in healthy subjects. Tolerability and safety are the main objectives of early clinical development but assessment
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of, in particular, PK already in the entry-into-humans trial has become standard. However, in this regard PD is too often treated as a stepchild and the different variables are approached in a fragmented
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or isolated way. Their integration into one coherent framework could generate valuable information
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on the basis of which proof-of-concept and dose-finding trials in patients can be designed. It is well established that a broad spectrum of extrinsic and intrinsic factors can have a marked influence on the
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PK of drugs. However, although there are clear indications that variability between subjects in PD may be at least as pronounced as in PK, this fact is still scarcely recognized and not sufficiently
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studied in the development of new drugs (Danhof 2015). The conduct of well-designed dose-finding trials in the target population can be considered key in the development process of new drugs.
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Without a solid base laid by clinical pharmacology and dose-finding studies, embarking on costly
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Phase 3 studies remains a risky undertaking. A key goal of clinical pharmacology in drug development can be described as determination of the dose (range) at which first patient studies are to
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be conducted. In the early clinical studies doses may be administered which will not be studied later in patients (in particular high doses) and, therefore, optimal use is to be made of the information
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generated. Pharmacokinetic-pharmacodynamic (PK/PD) modelling techniques can serve as a backbone, delivering quantitative assessments and model-based predictions. In the following we present case studies of an integrated PK/PD approach in the context of early clinical development of drugs from different therapeutic classes. They serve to illustrate that application of these principles enables targeted and efficient development of innovative drugs.
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ACCEPTED MANUSCRIPT 2. Almorexant in sleep disorders Compounds with an effect on the central nervous system (CNS) have a notorious reputation with respect to their chances of success in drug development, i.e., a low probability of reaching the market. Several factors are responsible for this, among others the validity of preclinical and early clinical models of the condition to be treated as well as the challenges of assessing drug effects in an objective
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and reproducible manner (Dingemanse et al., 1988a; Koopmans et al., 1988, 1991). Although there is still a high medical need for new drugs, several pharmaceutical companies have dismantled their
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research facilities in the CNS field. As a consequence, very few new CNS drugs have been launched
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in recent years.
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Almorexant was the first dual orexin receptor antagonist (DORA) that entered clinical development (Brisbare-Roch et al., 2007). Orexins are neuropeptides synthesized by a small number of neurons in
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the lateral hypothalamus (Carter et al., 2009; Tsujino and Sakurai, 2009). These neurons play an important role in energy homeostasis and the sleep-wake cycle. Almorexant rapidly progressed through a series of clinical pharmacology studies, some of which were conducted in parallel. The
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entry-into-human single-dose study explored the dose range of 5-1000 mg and, apart from tolerability, safety, and PK, extensively investigated PD by application of a CNS test battery that had been validated for the assessment of drug effects elicited by benzodiazepines (Mandema et al., 1992; van
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Steveninck et al., 1993). Sleep-promoting effects of drugs per se cannot be assessed in healthy subjects as they do not have a sleep disorder. However, by accurately measuring variables such as
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saccadic eye movements, adaptive tracking of a moving object, body sway in a standing position, and subjective alertness, and by including an active control (zolpidem) in the initial clinical study, predictions about the dose range to be studied in patients with insomnia disorders could be made at an early development stage (Hoever et al., 2010). Fig. 1 presents the time course of drug effect on visual analogue alertness for almorexant doses of 200-1000 mg. Subsequently, with only single-dose data in healthy subjects available, the first study in patients with primary insomnia and combining proof-ofconcept and dose-finding aspects was initiated (Hoever et al., 2012a). This study was also conducted on a single-dose basis but, in contrast to the entry-into-humans trials, had a descending-dose design. 3
ACCEPTED MANUSCRIPT Proof-of-concept of dual orexin receptor antagonism was shown at a dose of 400 mg and, thereafter, the effective dose range was shown to be 100-400 mg (Hoever et al., 2012a). After establishment of proof-of-concept and the relevant dose range, Phase 3 clinical studies were initiated (RESTORA-1), obviously in a multiple-dose design and based on multiple-dose studies in healthy subjects (Hoever et al., 2012b) performed in parallel to the initial patient trial. Tolerance development towards the effects
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of CNS drugs when administered on a chronic basis was studied before embarking on long-term patient trials (Dingemanse et al., 1990). Although the mechanism of drug action was innovative and
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the applicability of CNS measures developed for GABA receptor agonists was uncertain for a DORA,
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the sophisticated design of early clinical pharmacology studies and the use of PK/PD modelling
3. Setipiprant in allergic inflammation
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enabled an efficient and timely start of pivotal clinical trials.
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CRTH2 (chemoattractant receptor-homologous molecule expressed on T helper-2 cells) is a prostaglandin D2 receptor that plays an important role in allergic inflammation. Several CRTH2
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antagonists are in clinical development for the treatment of asthma, atopic dermatitis, and eosinophilic
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oesophagitis (Norman 2013; Santini et al., 2016). However, thus far the clinical efficacy of a range of compounds in these indications has been modest. These compounds share a relatively short
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pharmacokinetic half-life and, therefore, continuous CRTH2 antagonism, also upon b.i.d. dosing is a challenge (Sidharta et al., 2014). Setipiprant in a dosing regimen of 1000 mg b.i.d. was demonstrated
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to reduce allergen-induced airway responses in allergic asthmatics (Diamant et al., 2014). This confirmed that CRTH2 may be a promising target for the treatment of allergic disorders. Since studies in asthmatic conditions are very lengthy and expensive, setipiprant was first tested in a Phase 2 trial in seasonal allergic rhinitis (mountain cedar allergy). Good efficacy was again demonstrated for the 1000 mg b.i.d. dosing regimen but not confirmed in a subsequent Phase 3 study. At the time setipiprant entered clinical trials, a PD effect marker was not yet available in healthy subjects and dose escalation was mainly based on tolerability and PK considerations. During Phase 2 development, quantification of the effect on blocking PGD2-induced internalization of CRTH2 on eosinophils was
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ACCEPTED MANUSCRIPT established (Strasser et al., 2015). Knowledge generated on the basis of this assay was retrospectively applied to setipiprant and prospectively to a follow-up compound, ACT-453859 (Géhin et al., 2015; Krause et al., 2016a). Pharmacometric quantification showed the usefulness of CRTH2 internalization as a clinical biomarker, facilitating narrowing of the dose range to be explored in dose-finding trials. In addition, the modelling exercise made it plausible that the 1000 mg b.i.d. dosing regimen of
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setipiprant was borderline in terms of desired efficacy (Fig. 2), thus potentially explaining the
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discrepancies between Phase 2 and 3 results in effects on seasonal allergic rhinitis.
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4. ACT-451840 in malaria
Malaria remains among the diseases that have the largest impact on healthcare at a global level. Each
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year approximately 600,000 people, mainly children, die due to one of the malaria forms. Emergence of resistance against existing drugs used in the fight against malaria necessitates the development of
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new drugs, that, ideally, provide a cure by a single dose administration. ACT-451840 is a new chemical entity which potently inhibits both multidrug-resistant and sensitive
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Plasmodium falciparum asexual blood stage parasites (Le Bihan et al., 2016). Its mechanism of action has not yet been completely elucidated. Instead of performing an additional battery of in vitro and animal experiments, it was decided to explore the properties of this compound in early clinical trials
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aimed at obtaining relevant information for the treatment of malaria. Although only single-dose studies with ACT-451840 were conducted, these generated important data regarding further
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development possibilities. The entry-into-humans trial had a classical design in which doses of 10-500 mg were studied (Bruderer et al., 2015). The compound was well-tolerated and its relatively low bioavailability could be markedly increased when administered in fed state. Drug concentrations were also assessed by a bioassay suggesting the presence of circulating highly active metabolites. When studying PK/PD relationships, the possible role of (inter)active metabolites deserves close attention (Dingemanse et al., 1988c). Following the entry-into-humans trial, the traditional development of antimalarial drugs would encompass the conduct of multiple-dose studies in healthy subjects followed by a large Phase 2 trial in malaria patients. The latter type of study is logistically very demanding and 5
ACCEPTED MANUSCRIPT deals with highly variable conditions, thereby complicating proof-of-concept decisions. For these reasons a human blood stage challenge model in healthy subjects was designed as the second clinical study (McCarthy et al., 2011). Eight healthy male subjects were infected with blood stage P. falciparum and treated with a single dose of ACT-451840 after 7 days. The PK/PD modelling approach combined a model of parasite growth (i.e., disease progression) with the effect of the drug
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(Krause et al., 2016b). Simulations were performed to estimate the likelihood of achieving cure in larger populations under different dosing regimens. Single-dose treatment with ACT-451840 was
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associated with a marked reduction in the level of parasitaemia with a parasite clearance half-life of
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7.7 h. However, the study clearly showed that, due to the development of recrudescence, single-dose treatment was insufficiently potent or prolonged to achieve complete parasite clearance. Model-based
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predictions showed that 6 daily doses of 500 mg of ACT-451840 would be sufficient to achieve cure in more than 90 % of subjects (Fig. 3). This study conducted in only 8 healthy subjects showed that
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the strategy chosen can support decision making very early in the clinical development process of a
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new drug.
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5. ACT-280778 in cardiovascular disease
Currently available calcium channel blockers in the treatment of cardiovascular disorders target the L-
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type (slowly inactivating or high-voltage activated) channels. T-type calcium channel blocking in addition could yield an improved efficacy and safety profile (McGivern, 2006; Ge and Ren, 2009).
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ACT-280778 is a novel dual L/T-type calcium channel blocker that was investigated in 2 clinical pharmacology studies in healthy subjects (Mueller et al., 2014). Dose escalation was guided by PK and PD modelling. Preclinical data were used to mathematically define the a priori knowledge of PD effects. A Bayesian methodology combined the prior knowledge with the data as they accumulated over successive dose groups in the single-ascending dose study (Berry, 2006a). The resulting posterior distributions of PD effects were then used to predict the most desirable dose, the dose providing an optimal benefit-risk ratio (Thall et al., 2006). A variation of the logistic regression algorithm (Tibaldi et al., 2008) using Emax models was implemented.
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ACCEPTED MANUSCRIPT The model and its predictions were updated after each dose group (Mueller et al., 2014), estimating the maximum tolerated dose (MTD) and allowing to judge how close the MTD was to the last dose administered. From the third dose group onwards, the dose was escalated based on the most desirable dose estimated by modelling, however, not exceeding 3 times the previous dose level. The results for PD (QTc,B, QTc,F, PR interval length, and systolic and diastolic blood pressure) were
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summarized in form of a regression model fit superimposed with observed data, an estimation of the
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probability of being the MTD for a set of candidate future doses, and, for the set of candidate doses, the estimated probability that the dose would still be acceptable based on pre-defined acceptability
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criteria (Fig. 4).
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The subsequent MAD study was planned using a risk modelling approach: the single-dose PK model with characterization of the effect of food was used to simulate multiple-dose scenarios with different
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doses, numbers of subjects, and food status (fasted and fed, the latter increasing exposure). Simulation of different study setups allowed for estimating the probability of exceeding the exposure observed in
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the 40 mg single dose group that led to early termination of that study. This quantitative assessment
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enabled the clinical team to proceed with greater confidence in the conduct of the MAD study that was conducted in 7 subjects on active and 3 on placebo in each of two dose groups, 5 and 15 mg
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(Mueller et al., 2014).
The model-guided dose escalation provided a quantitative backbone that enabled a more efficient
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study conduct due to possibly larger dose increases early on and estimation of the MTD throughout the study (i.e., before the MTD was finally determined based on data). The MTD could even be estimated with greater accuracy based on the model: the empirical approach defines the MTD to be the largest administered dose that was tolerable. However, the true MTD is in between the largest administered tolerable dose and the lowest administered non-tolerable dose and can be estimated in a straightforward fashion by using a modelling and simulation approach.
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ACCEPTED MANUSCRIPT 6. ACT-246475 in atherothrombotic events Atherothrombotic events such as acute coronary syndromes are commonly treated with a P2Y12 platelet receptor antagonist (Antman et al., 2004; Michelson, 2010). The irreversible thienopyridines clopidogrel and prasugrel as well as the reversible antagonist ticagrelor at higher doses and at higher levels of inhibition of platelet aggregation have revealed increased risk of bleeding and morbidity
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following bleeding events (Crouch et al., 2011). Therefore, the need of a potent and reversible antiplatelet agent with fast onset of action, low variability of response, and an improved safety profile
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compared to thienopyridines and ticagrelor remains unmet (Di Minno et al., 2011).
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ACT-246475 is a reversible, selective, and potent inhibitor of the platelet P2Y12 receptor and, in
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preclinical investigations, exhibited favourable characteristics compared to currently available P2Y12 antagonists. The entry-into-man study compared the PK of an oral formulation of ACT-281959, a
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double-ester prodrug of the active moiety, vs placebo in 40 healthy subjects in part I. After establishing a relevant dose, part II enrolled 9 healthy subjects in a 3-way-crossover study comparing exploratory formulations of ACT-281959 and ACT-246475 (Baldoni et al., 2014). ADP-induced
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platelet aggregation was measured ex vivo with 2 different methods: Light Transmission Aggregometry (reference gold standard) and VerifyNow P2Y12 (novel point-of-care) (Michelson, 2009).
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The PK/PD relationship linking drug concentration to percentage of inhibition of platelet aggregation
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(%IPA) was described by a sigmoid Emax model. A Bayesian approach (Berry, 2006a, b) combined information from the in vitro IC50 measurements in form of a mathematical prior function with clinical ex vivo data. The joint model allowed for an assessment of the consistency of ex vivo and in vivo model fits (Fig. 5) and enabled PK/PD model estimation with limited clinical data. This facilitated the design of subsequent clinical studies.
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ACCEPTED MANUSCRIPT 7. Conclusions In this short review we have presented selected examples of applying an integrated PK/PD approach in the early clinical development of drugs. The cases show that such strategy can be employed for a spectrum of therapeutic drug classes (sleep-promoting, anti-allergic, anti-malarial, anti-hypertensive, and anti-coagulation drugs). It is sometimes claimed that modelling concepts are mainly of value
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when dealing with data generated from patients in the target population. However, the cases presented demonstrate that a wealth of information can be obtained about the future development potential of
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new drug candidates by careful design of early clinical pharmacology studies in healthy subjects.
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Knowledge about the dose range to be explored further in early patient trials is key and considerable resources can be saved by the pragmatic application of the principles presented (Breimer and Danhof,
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1997; Dingemanse and Appel-Dingemanse, 2007).
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The principles laid down here for early clinical development can, with the appropriate adjustments, also be applied to later stages of clinical development, in which variability caused by disease factors comes into play (Dingemanse et al., 1988b). Levy and Danhof are among the pioneers who advanced
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the investigation of kinetics of drug action in physiological and disease states spanning the time from the 1960s until now (Levy 1966; Danhof 2015). Physiology-based PD models form the latest development in this continuously evolving discipline that has major implications for the science of
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drug development.
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8. Acknowledgement
Meindert Danhof as a supervisor of the PhD thesis of the first author of this review has been instrumental in laying the basis of a career in preclinical and clinical pharmacology. Drug development at different pharmaceutical companies has profited greatly from the application of PK/PD modelling principles with which the author was initially confronted at the Leiden Academic Centre for Drug Research, Leiden, the Netherlands.
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Strasser, D.S., Farine, H., Holdener, M., Zisowsky, J., Roscher, R., Hoerner, J., Gehin, M., Sidharta, P.N., Dingemanse, J., Groenen, P.M.A., 2015. Development of a decision-making biomarker for CRTH2 antagonism in clinical studies. New Horiz. Transl. Med. 2(4-5), 118-125. Thall, P.F., Cook, J.D., Estey, E.H., 2006. Adaptive dose selection using efficacy-toxicity trade-offs: illustrations and practical considerations. J. Biopharm. Stat. 16(5), 623-638.
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ACCEPTED MANUSCRIPT Tibaldi, F.S., Beck, B.H., Bedding, A., 2008. Implementation of a Phase 1 adaptive clinical trial in a treatment of type 2 diabetes. Drug Inf. J. 42(5), 455-465. Tsujino, N., Sakurai T., 2009. Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacol. Rev. 61(2), 162-176.
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Van Steveninck, A.L., Mandema, J.W., Tuk, B., Van Dijk, J.G., Schoemaker, H.C., Danhof, M., Cohen, A.F., 1993. A comparison of the concentration-effect relationships of midazolam for EEG-
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derived parameters and saccadic peak velocity. Br. J. Clin. Pharmacol. 36(2), 109-115.
10. Figure captions
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Fig. 1: Linear pharmacokinetic-pharmacodynamic model with linear time effect: observed (symbols) time course and predicted (line) time course of the mean change from baseline for visual analogue
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scale alertness after administration of 200, 400, and 1000 mg of almorexant. The observed values represent the mean of data from n=14 subjects on placebo and n=6 subjects on the almorexant doses.
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Reproduced with permission from Hoever et al., 2010.
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Fig. 2: a Combined concentration (conc.) of ACT-453859/ACT-463036 (active metabolite) and b concentration of setipiprant versus percentage of CRTH2 receptors on eosinophils. In the maximum
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effect (Emax) model (top graphs), green lines indicate the model fit and the 90 % confidence interval, and observed data are shown as symbols, which correspond to the dose groups in the box-and-whisker
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plots (bottom graphs), showing drug concentrations by dose group; symbols indicate medians, boxes indicate 50 % ranges around the medians, whiskers approximately indicate 95 % intervals. Reproduced with permission from Krause et al., 2016a. Fig. 3: Simulated parasite concentration, population-typical and 80 % range for one to six doses of 500 mg once daily. Reproduced with permission from Krause et al., 2016b. Fig. 4: Modelling and simulation results for maximum individual decrease in systolic blood pressure in supine position after administration of 40 mg. a observed maximum individual decrease versus
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ACCEPTED MANUSCRIPT dose administered and Emax regression fit; b probability estimate for candidate doses 0, 5, …, 100 mg to be clinically acceptable (<25 % of subjects showing a maximum decrease of 20 mmHg or higher); c estimated distribution of MTD for candidate doses. Reproduced with permission from Mueller et al., 2014. Fig. 5: %IPA(M) (left) and %IPAPRU (right) in citrate versus ACT-246475 concentrations (semi-
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logarithmic scale) during assay validation and in the clinical study with Imax model fits. %IPA
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percent inhibition of platelet aggregation, %IPA(M) IPA calculated using MPA, %IPAPRU IPA calculated using PRU, MPA maximal platelet aggregation (LTA method), PRU device derived P2Y12
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Jasper Dingemanse, Andreas Krause PII: DOI: Reference:
S0928-0987(17)30270-1 doi: 10.1016/j.ejps.2017.05.042 PHASCI 4056
To appear in:
European Journal of Pharmaceutical Sciences
Received date: Revised date: Accepted date:
19 May 2017 ###REVISEDDATE### 19 May 2017
Please cite this article as: Jasper Dingemanse, Andreas Krause , Impact of pharmacokinetic-pharmacodynamic modelling in early clinical drug development, European Journal of Pharmaceutical Sciences (2017), doi: 10.1016/j.ejps.2017.05.042
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ACCEPTED MANUSCRIPT Impact of pharmacokinetic-pharmacodynamic modelling in early clinical drug development Jasper Dingemanse, PhD, PharmD, FCP, Andreas Krause, PhD Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123
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Allschwil, Switzerland
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Author for correspondence:
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Jasper Dingemanse, PhD, PharmD, FCP, Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland
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Email: [email protected], Tel. +41 61 565 64 63, Fax: +41 61 565 62 00
Abstract
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Early clinical pharmacology studies in healthy subjects are often dissociated from patient studies. In
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this review we encourage the use of modelling and simulation techniques to generate valuable information at an early stage of clinical development. We illustrate these principles by presenting 5
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different case studies from a spectrum of therapeutic drug classes. Their application leads to a better understanding of drug characteristics early on, thereby facilitating the design of dose-finding studies
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in the target patient population and saving resources.
Keywords Clinical pharmacology; drug development; modelling; pharmacokinetics; pharmacodynamics
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ACCEPTED MANUSCRIPT 1. Introduction The science of clinical pharmacology traditionally encompasses the assessment of tolerability, safety, pharmacokinetics (PK), and pharmacodynamics (PD). For most therapeutic areas and drug classes this information is obtained by the conduct of single- and multiple-ascending dose studies in healthy subjects. Tolerability and safety are the main objectives of early clinical development but assessment
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of, in particular, PK already in the entry-into-humans trial has become standard. However, in this regard PD is too often treated as a stepchild and the different variables are approached in a fragmented
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or isolated way. Their integration into one coherent framework could generate valuable information
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on the basis of which proof-of-concept and dose-finding trials in patients can be designed. It is well established that a broad spectrum of extrinsic and intrinsic factors can have a marked influence on the
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PK of drugs. However, although there are clear indications that variability between subjects in PD may be at least as pronounced as in PK, this fact is still scarcely recognized and not sufficiently
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studied in the development of new drugs (Danhof 2015). The conduct of well-designed dose-finding trials in the target population can be considered key in the development process of new drugs.
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Without a solid base laid by clinical pharmacology and dose-finding studies, embarking on costly
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Phase 3 studies remains a risky undertaking. A key goal of clinical pharmacology in drug development can be described as determination of the dose (range) at which first patient studies are to
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be conducted. In the early clinical studies doses may be administered which will not be studied later in patients (in particular high doses) and, therefore, optimal use is to be made of the information
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generated. Pharmacokinetic-pharmacodynamic (PK/PD) modelling techniques can serve as a backbone, delivering quantitative assessments and model-based predictions. In the following we present case studies of an integrated PK/PD approach in the context of early clinical development of drugs from different therapeutic classes. They serve to illustrate that application of these principles enables targeted and efficient development of innovative drugs.
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ACCEPTED MANUSCRIPT 2. Almorexant in sleep disorders Compounds with an effect on the central nervous system (CNS) have a notorious reputation with respect to their chances of success in drug development, i.e., a low probability of reaching the market. Several factors are responsible for this, among others the validity of preclinical and early clinical models of the condition to be treated as well as the challenges of assessing drug effects in an objective
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and reproducible manner (Dingemanse et al., 1988a; Koopmans et al., 1988, 1991). Although there is still a high medical need for new drugs, several pharmaceutical companies have dismantled their
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research facilities in the CNS field. As a consequence, very few new CNS drugs have been launched
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in recent years.
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Almorexant was the first dual orexin receptor antagonist (DORA) that entered clinical development (Brisbare-Roch et al., 2007). Orexins are neuropeptides synthesized by a small number of neurons in
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the lateral hypothalamus (Carter et al., 2009; Tsujino and Sakurai, 2009). These neurons play an important role in energy homeostasis and the sleep-wake cycle. Almorexant rapidly progressed through a series of clinical pharmacology studies, some of which were conducted in parallel. The
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entry-into-human single-dose study explored the dose range of 5-1000 mg and, apart from tolerability, safety, and PK, extensively investigated PD by application of a CNS test battery that had been validated for the assessment of drug effects elicited by benzodiazepines (Mandema et al., 1992; van
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Steveninck et al., 1993). Sleep-promoting effects of drugs per se cannot be assessed in healthy subjects as they do not have a sleep disorder. However, by accurately measuring variables such as
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saccadic eye movements, adaptive tracking of a moving object, body sway in a standing position, and subjective alertness, and by including an active control (zolpidem) in the initial clinical study, predictions about the dose range to be studied in patients with insomnia disorders could be made at an early development stage (Hoever et al., 2010). Fig. 1 presents the time course of drug effect on visual analogue alertness for almorexant doses of 200-1000 mg. Subsequently, with only single-dose data in healthy subjects available, the first study in patients with primary insomnia and combining proof-ofconcept and dose-finding aspects was initiated (Hoever et al., 2012a). This study was also conducted on a single-dose basis but, in contrast to the entry-into-humans trials, had a descending-dose design. 3
ACCEPTED MANUSCRIPT Proof-of-concept of dual orexin receptor antagonism was shown at a dose of 400 mg and, thereafter, the effective dose range was shown to be 100-400 mg (Hoever et al., 2012a). After establishment of proof-of-concept and the relevant dose range, Phase 3 clinical studies were initiated (RESTORA-1), obviously in a multiple-dose design and based on multiple-dose studies in healthy subjects (Hoever et al., 2012b) performed in parallel to the initial patient trial. Tolerance development towards the effects
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of CNS drugs when administered on a chronic basis was studied before embarking on long-term patient trials (Dingemanse et al., 1990). Although the mechanism of drug action was innovative and
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the applicability of CNS measures developed for GABA receptor agonists was uncertain for a DORA,
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the sophisticated design of early clinical pharmacology studies and the use of PK/PD modelling
3. Setipiprant in allergic inflammation
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enabled an efficient and timely start of pivotal clinical trials.
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CRTH2 (chemoattractant receptor-homologous molecule expressed on T helper-2 cells) is a prostaglandin D2 receptor that plays an important role in allergic inflammation. Several CRTH2
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antagonists are in clinical development for the treatment of asthma, atopic dermatitis, and eosinophilic
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oesophagitis (Norman 2013; Santini et al., 2016). However, thus far the clinical efficacy of a range of compounds in these indications has been modest. These compounds share a relatively short
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pharmacokinetic half-life and, therefore, continuous CRTH2 antagonism, also upon b.i.d. dosing is a challenge (Sidharta et al., 2014). Setipiprant in a dosing regimen of 1000 mg b.i.d. was demonstrated
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to reduce allergen-induced airway responses in allergic asthmatics (Diamant et al., 2014). This confirmed that CRTH2 may be a promising target for the treatment of allergic disorders. Since studies in asthmatic conditions are very lengthy and expensive, setipiprant was first tested in a Phase 2 trial in seasonal allergic rhinitis (mountain cedar allergy). Good efficacy was again demonstrated for the 1000 mg b.i.d. dosing regimen but not confirmed in a subsequent Phase 3 study. At the time setipiprant entered clinical trials, a PD effect marker was not yet available in healthy subjects and dose escalation was mainly based on tolerability and PK considerations. During Phase 2 development, quantification of the effect on blocking PGD2-induced internalization of CRTH2 on eosinophils was
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ACCEPTED MANUSCRIPT established (Strasser et al., 2015). Knowledge generated on the basis of this assay was retrospectively applied to setipiprant and prospectively to a follow-up compound, ACT-453859 (Géhin et al., 2015; Krause et al., 2016a). Pharmacometric quantification showed the usefulness of CRTH2 internalization as a clinical biomarker, facilitating narrowing of the dose range to be explored in dose-finding trials. In addition, the modelling exercise made it plausible that the 1000 mg b.i.d. dosing regimen of
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setipiprant was borderline in terms of desired efficacy (Fig. 2), thus potentially explaining the
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discrepancies between Phase 2 and 3 results in effects on seasonal allergic rhinitis.
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4. ACT-451840 in malaria
Malaria remains among the diseases that have the largest impact on healthcare at a global level. Each
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year approximately 600,000 people, mainly children, die due to one of the malaria forms. Emergence of resistance against existing drugs used in the fight against malaria necessitates the development of
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new drugs, that, ideally, provide a cure by a single dose administration. ACT-451840 is a new chemical entity which potently inhibits both multidrug-resistant and sensitive
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Plasmodium falciparum asexual blood stage parasites (Le Bihan et al., 2016). Its mechanism of action has not yet been completely elucidated. Instead of performing an additional battery of in vitro and animal experiments, it was decided to explore the properties of this compound in early clinical trials
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aimed at obtaining relevant information for the treatment of malaria. Although only single-dose studies with ACT-451840 were conducted, these generated important data regarding further
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development possibilities. The entry-into-humans trial had a classical design in which doses of 10-500 mg were studied (Bruderer et al., 2015). The compound was well-tolerated and its relatively low bioavailability could be markedly increased when administered in fed state. Drug concentrations were also assessed by a bioassay suggesting the presence of circulating highly active metabolites. When studying PK/PD relationships, the possible role of (inter)active metabolites deserves close attention (Dingemanse et al., 1988c). Following the entry-into-humans trial, the traditional development of antimalarial drugs would encompass the conduct of multiple-dose studies in healthy subjects followed by a large Phase 2 trial in malaria patients. The latter type of study is logistically very demanding and 5
ACCEPTED MANUSCRIPT deals with highly variable conditions, thereby complicating proof-of-concept decisions. For these reasons a human blood stage challenge model in healthy subjects was designed as the second clinical study (McCarthy et al., 2011). Eight healthy male subjects were infected with blood stage P. falciparum and treated with a single dose of ACT-451840 after 7 days. The PK/PD modelling approach combined a model of parasite growth (i.e., disease progression) with the effect of the drug
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(Krause et al., 2016b). Simulations were performed to estimate the likelihood of achieving cure in larger populations under different dosing regimens. Single-dose treatment with ACT-451840 was
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associated with a marked reduction in the level of parasitaemia with a parasite clearance half-life of
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7.7 h. However, the study clearly showed that, due to the development of recrudescence, single-dose treatment was insufficiently potent or prolonged to achieve complete parasite clearance. Model-based
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predictions showed that 6 daily doses of 500 mg of ACT-451840 would be sufficient to achieve cure in more than 90 % of subjects (Fig. 3). This study conducted in only 8 healthy subjects showed that
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the strategy chosen can support decision making very early in the clinical development process of a
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new drug.
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5. ACT-280778 in cardiovascular disease
Currently available calcium channel blockers in the treatment of cardiovascular disorders target the L-
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type (slowly inactivating or high-voltage activated) channels. T-type calcium channel blocking in addition could yield an improved efficacy and safety profile (McGivern, 2006; Ge and Ren, 2009).
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ACT-280778 is a novel dual L/T-type calcium channel blocker that was investigated in 2 clinical pharmacology studies in healthy subjects (Mueller et al., 2014). Dose escalation was guided by PK and PD modelling. Preclinical data were used to mathematically define the a priori knowledge of PD effects. A Bayesian methodology combined the prior knowledge with the data as they accumulated over successive dose groups in the single-ascending dose study (Berry, 2006a). The resulting posterior distributions of PD effects were then used to predict the most desirable dose, the dose providing an optimal benefit-risk ratio (Thall et al., 2006). A variation of the logistic regression algorithm (Tibaldi et al., 2008) using Emax models was implemented.
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ACCEPTED MANUSCRIPT The model and its predictions were updated after each dose group (Mueller et al., 2014), estimating the maximum tolerated dose (MTD) and allowing to judge how close the MTD was to the last dose administered. From the third dose group onwards, the dose was escalated based on the most desirable dose estimated by modelling, however, not exceeding 3 times the previous dose level. The results for PD (QTc,B, QTc,F, PR interval length, and systolic and diastolic blood pressure) were
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summarized in form of a regression model fit superimposed with observed data, an estimation of the
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probability of being the MTD for a set of candidate future doses, and, for the set of candidate doses, the estimated probability that the dose would still be acceptable based on pre-defined acceptability
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criteria (Fig. 4).
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The subsequent MAD study was planned using a risk modelling approach: the single-dose PK model with characterization of the effect of food was used to simulate multiple-dose scenarios with different
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doses, numbers of subjects, and food status (fasted and fed, the latter increasing exposure). Simulation of different study setups allowed for estimating the probability of exceeding the exposure observed in
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the 40 mg single dose group that led to early termination of that study. This quantitative assessment
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enabled the clinical team to proceed with greater confidence in the conduct of the MAD study that was conducted in 7 subjects on active and 3 on placebo in each of two dose groups, 5 and 15 mg
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(Mueller et al., 2014).
The model-guided dose escalation provided a quantitative backbone that enabled a more efficient
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study conduct due to possibly larger dose increases early on and estimation of the MTD throughout the study (i.e., before the MTD was finally determined based on data). The MTD could even be estimated with greater accuracy based on the model: the empirical approach defines the MTD to be the largest administered dose that was tolerable. However, the true MTD is in between the largest administered tolerable dose and the lowest administered non-tolerable dose and can be estimated in a straightforward fashion by using a modelling and simulation approach.
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ACCEPTED MANUSCRIPT 6. ACT-246475 in atherothrombotic events Atherothrombotic events such as acute coronary syndromes are commonly treated with a P2Y12 platelet receptor antagonist (Antman et al., 2004; Michelson, 2010). The irreversible thienopyridines clopidogrel and prasugrel as well as the reversible antagonist ticagrelor at higher doses and at higher levels of inhibition of platelet aggregation have revealed increased risk of bleeding and morbidity
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following bleeding events (Crouch et al., 2011). Therefore, the need of a potent and reversible antiplatelet agent with fast onset of action, low variability of response, and an improved safety profile
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compared to thienopyridines and ticagrelor remains unmet (Di Minno et al., 2011).
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ACT-246475 is a reversible, selective, and potent inhibitor of the platelet P2Y12 receptor and, in
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preclinical investigations, exhibited favourable characteristics compared to currently available P2Y12 antagonists. The entry-into-man study compared the PK of an oral formulation of ACT-281959, a
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double-ester prodrug of the active moiety, vs placebo in 40 healthy subjects in part I. After establishing a relevant dose, part II enrolled 9 healthy subjects in a 3-way-crossover study comparing exploratory formulations of ACT-281959 and ACT-246475 (Baldoni et al., 2014). ADP-induced
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platelet aggregation was measured ex vivo with 2 different methods: Light Transmission Aggregometry (reference gold standard) and VerifyNow P2Y12 (novel point-of-care) (Michelson, 2009).
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The PK/PD relationship linking drug concentration to percentage of inhibition of platelet aggregation
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(%IPA) was described by a sigmoid Emax model. A Bayesian approach (Berry, 2006a, b) combined information from the in vitro IC50 measurements in form of a mathematical prior function with clinical ex vivo data. The joint model allowed for an assessment of the consistency of ex vivo and in vivo model fits (Fig. 5) and enabled PK/PD model estimation with limited clinical data. This facilitated the design of subsequent clinical studies.
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ACCEPTED MANUSCRIPT 7. Conclusions In this short review we have presented selected examples of applying an integrated PK/PD approach in the early clinical development of drugs. The cases show that such strategy can be employed for a spectrum of therapeutic drug classes (sleep-promoting, anti-allergic, anti-malarial, anti-hypertensive, and anti-coagulation drugs). It is sometimes claimed that modelling concepts are mainly of value
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when dealing with data generated from patients in the target population. However, the cases presented demonstrate that a wealth of information can be obtained about the future development potential of
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new drug candidates by careful design of early clinical pharmacology studies in healthy subjects.
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Knowledge about the dose range to be explored further in early patient trials is key and considerable resources can be saved by the pragmatic application of the principles presented (Breimer and Danhof,
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1997; Dingemanse and Appel-Dingemanse, 2007).
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The principles laid down here for early clinical development can, with the appropriate adjustments, also be applied to later stages of clinical development, in which variability caused by disease factors comes into play (Dingemanse et al., 1988b). Levy and Danhof are among the pioneers who advanced
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the investigation of kinetics of drug action in physiological and disease states spanning the time from the 1960s until now (Levy 1966; Danhof 2015). Physiology-based PD models form the latest development in this continuously evolving discipline that has major implications for the science of
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drug development.
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8. Acknowledgement
Meindert Danhof as a supervisor of the PhD thesis of the first author of this review has been instrumental in laying the basis of a career in preclinical and clinical pharmacology. Drug development at different pharmaceutical companies has profited greatly from the application of PK/PD modelling principles with which the author was initially confronted at the Leiden Academic Centre for Drug Research, Leiden, the Netherlands.
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ACCEPTED MANUSCRIPT 9. References Antman, E.M., Anbe, D.T., Armstrong, P.W., Bates, E.R., Green, L.A., Hand, M., Hochman, J.S., Krumholz, H.M., Kushner, F.G., Lamas, G.A., Mullany, C.J., Ornato, J.P., Pearle, D.L., Sloan, M.A., Smith, S.C., Jr., Alpert, J.S., Anderson, J.L., Faxon, D.P., Fuster, V., Gibbons, R.J., Gregoratos, G., Halperin, J.L., Hiratzka, L.F., Hunt, S.A., Jacobs, A.K., American College of Cardiology, American
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ACCEPTED MANUSCRIPT Krause, A., Zisowsky, J., Strasser, D.S., Gehin, M., Sidharta, P.N., Groenen, P.M., Dingemanse, J., 2016a. Pharmacokinetic/pharmacodynamic modelling of receptor internalization with CRTH2 antagonists to optimize dose selection. Clin. Pharmacokinet. 55(7), 813-821. Krause, A., Dingemanse, J., Mathis, A., Marquart, L., Möhrle, J.J., McCarthy, J.S., 2016b. Pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of Actelion-451840 in an
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Moehrle, J.J., Ng, C.L., Noviyanti, R., Ruecker, A., Sanz, L.M., Sauerwein, R.W., Scheurer, C., Schleiferboeck, S., Sinden, R., Snyder, C., Straimer, J., Wirjanata, G., Marfurt, J., Price, R.N., Weller,
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10. Figure captions
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Fig. 1: Linear pharmacokinetic-pharmacodynamic model with linear time effect: observed (symbols) time course and predicted (line) time course of the mean change from baseline for visual analogue
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scale alertness after administration of 200, 400, and 1000 mg of almorexant. The observed values represent the mean of data from n=14 subjects on placebo and n=6 subjects on the almorexant doses.
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Reproduced with permission from Hoever et al., 2010.
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Fig. 2: a Combined concentration (conc.) of ACT-453859/ACT-463036 (active metabolite) and b concentration of setipiprant versus percentage of CRTH2 receptors on eosinophils. In the maximum
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effect (Emax) model (top graphs), green lines indicate the model fit and the 90 % confidence interval, and observed data are shown as symbols, which correspond to the dose groups in the box-and-whisker
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plots (bottom graphs), showing drug concentrations by dose group; symbols indicate medians, boxes indicate 50 % ranges around the medians, whiskers approximately indicate 95 % intervals. Reproduced with permission from Krause et al., 2016a. Fig. 3: Simulated parasite concentration, population-typical and 80 % range for one to six doses of 500 mg once daily. Reproduced with permission from Krause et al., 2016b. Fig. 4: Modelling and simulation results for maximum individual decrease in systolic blood pressure in supine position after administration of 40 mg. a observed maximum individual decrease versus
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ACCEPTED MANUSCRIPT dose administered and Emax regression fit; b probability estimate for candidate doses 0, 5, …, 100 mg to be clinically acceptable (<25 % of subjects showing a maximum decrease of 20 mmHg or higher); c estimated distribution of MTD for candidate doses. Reproduced with permission from Mueller et al., 2014. Fig. 5: %IPA(M) (left) and %IPAPRU (right) in citrate versus ACT-246475 concentrations (semi-
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logarithmic scale) during assay validation and in the clinical study with Imax model fits. %IPA
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percent inhibition of platelet aggregation, %IPA(M) IPA calculated using MPA, %IPAPRU IPA calculated using PRU, MPA maximal platelet aggregation (LTA method), PRU device derived P2Y12
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