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Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

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Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin The AAPS Journal ( # 2016) DOI: 10.1208/s12248-016-9965-3 Research Article Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin Andrés Olivares-Morales,1,2,5 Avijit Ghosh,3 Leon Aarons,1 and Amin Rostami-Hodjegan1,4 Received 27 April 2016; accepted 21 July 2016 Abstract. A new minimal Segmented Transit and Absorption model (mSAT) model has been recently proposed and combined with intrinsic intestinal effective permeability (Peff,int) to predict the regional gastrointestinal (GI) absorption (fabs) of several drugs. Herein, this model was extended and applied for the prediction of oral bioavailability and pharmacoki- netics of oxybutynin and its enantiomers to provide a mechanistic explanation of the higher relative bioavailability observed for oxybutynin’s modified-release OROS® formulation compared to its immediate-release (IR) counterpart. The expansion of the model involved the incorporation of mechanistic equations for the prediction of release, transit, dissolution, permeation and first-pass metabolism. The predicted pharmacokinetics of oxybutynin enantiomers after oral administration for both the IR and OROS® formulations were in close agreement with the observed data. The predicted absolute bioavailability for the IR formulation was within 5% of the observed value, and the model adequately predicted the higher relative bioavailability observed for the OROS® formulation vs. the IR counterpart. From the model predictions, it can be noticed that the higher bioavailability observed for the OROS® formulation was mainly attributable to differences in the intestinal availability (FG) rather than due to a higher colonic fabs, thus confirming previous hypotheses. The predicted fabs was almost 70% lower for the OROS® formulation compared to the IR formulation, whereas the FG was almost eightfold higher than in the IR formulation. These results provide further support to the hypothesis of an increased FG as the main factor responsible for the higher bioavailability of oxybutynin’s OROS® formulation vs. the IR. KEY WORDS: CYP3A; formulation; intestinal metabolism; OROS®; oxybutynin; PBPK model. INTRODUCTION industry and regulatory agencies have highlighted the benefits of applying such models in the drug discovery and develop- In recent years, there has been an increase in the use of ment arena (1–6). By incorporating some of the mechanisms physiologically based pharmacokinetics (PBPK) models in driving the pharmacokinetics of a drug, PBPK models allows drug development, particularly in the pre-clinical and early one to distinguish between drug-related and the physiological clinical stages. Numerous articles coming from academia, factors controlling drug absorption, distribution, metabolism Electronic supplementary material The online version of this article Carboxylesterase 2; Cmax, Maximum plasma/blood concentration; CO, (doi:10.1208/s12248-016-9965-3) contains supplementary material, Cardiac output; CPGA, 2-Cyclohexyl-2-phenylglycolic acid; CR, Con- trolled release; DEOB,N-Desethyloxybutynin; F, Absolute oral bio- which is available to authorized users. availability; fabs, Fraction of the dose absorbed in the gastrointestinal 1 fi Centre for Applied Pharmacokinetic Research, Manchester Phar- tract; FG, Fraction of the dose absorbed that escapes gut wall rst- macy School, The University of Manchester, Manchester, UK. pass metabolism; FH Fraction of the dose absorbed that escapes 2 Present Address: Roche Pharma Research and Early Development hepatic first-pass metabolism; FOCE-I, First-order conditional with (pRED), Roche Innovation Center Basel. F. Hoffmann-La Roche interaction maximum likelihood estimation method; Frel Relative Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland. bioavailability; GI, Gastrointestinal; HLM, Human liver micro- 3 Janssen Pharmaceutica, Spring House, Pennsylvania, USA. somes; IR, Immediate release; IV or iv, Intravenous; LC-MS/MS, 4 Certara, Sheffield, UK. Liquid chromatography with tandem mass spectrometry detection; 5To whom correspondence should be addressed. (e-mail: M&S, Modelling and simulation; MR, Modified release; mSAT, [email protected]) Minimal segmented absorption and transit; OrBiTo, Oral ABBREVIATIONS ACAT, Advanced Compartmental Absorption and biopharmaceutics tools; OROS, Osmotic controlled-release oral Transit; ADAM, Advanced Dissolution Absorption and Metabolism; delivery system; OXY, Oxybutynin; PBPK, Physiologically based AGP, α1-Acidglycoprotein; AUC, Area under the curve; BCS, pharmacokinetic(s); Peff, intestinal effective permeability; SI, Small Biopharmaceutical Classification System; BW, Body weight; CES1, intestine (al); SITT, Small intestinal transit time 1550-7416/16/0000-0001/0 # 2016 The Author(s). This article is published with open access at Springerlink.com Olivares-Morales et al. and elimination (ADME). This characteristic enables one to translation of regional intestinal variations in the available integrate measured in vitro or in silico drug properties into mucosal surface area (mSA) into segment-dependent permeabil- the model in the so-called in vitro–in vivo extrapolation ity and absorption (26). When the approaches were combined (IVIVE) approach, enabling the use of such models in a truly with a novel simplified absorption PBPK model, or minimal prospective fashion (6). PBPK models have been increasingly Segmented Absorption and Transit (mSAT) model, they showed applied in oral absorption and biopharmaceutics. This has a potential to decrease the observed overestimation of the colonic been partly due to the development and availability of fabs (26), especially when applying the so-called Method 3 (M3) mechanistic absorption models such as the ones included in which was based on the intestinal mSA values derived recently by commercial software packages like SimCYP® (ADAM) (7), Helander and Fändriks (26,27). GastroPlus™ (ACAT) (8) and PK-Sim® (9,10), as well as One of the limitations of the prospective PBPK analysis of some in-house developments coming from academia and the bioavailability differences between IR and MR formulations industry (11–14). of CYP3A substrates was the lack of drug-specificsimulations Oral absorption and bioavailability are dependent upon necessary to provide stronger support for the prospective numerous physiological and drug-related factors interacting modelling and simulation study outcome (21). Therefore, the simultaneously. These factors are the key to defining the present work was designed as a continuation of the work different steps of the oral absorption process, i.e. transit, performed in the previous studies, with the main aim to provide dissolution, release, permeation, transport and metabolism a drug-specific example to support the hypothesis of a reduced (15,16). Given the complex nature of these drug–physiology first-pass metabolism as the main driving mechanism of the interactions, prospective predictions of oral bioavailability higher Frel of CYP3A substrates formulated as MR (21). within the PBPK framework are still a challenging task (17– In particular, this study investigated the bioavailability 19). Nevertheless, significant efforts have recently been made differences observed for the MR formulation of oxybutynin in order to improve our understanding of such a complex (OXY). OXY is a highly cleared antimuscarinic drug with interplay. For instance, the Innovative Medicines Initiative anticholinergic, spasmolytic and local anaesthetic properties (IMI) OrBiTo project has amongst its goals to enrich our employed for the treatment of urge urinary incontinency due to over activity of the detrusor muscle (28). OXY is a highly knowledge of the physiological and biopharmaceutical prop- permeable and soluble compound (BCS Class 1) (21). After oral erties that define in vivo drug absorption and to provide new administration, OXY is rapidly absorbed and undergoes exten- in vitro and in silico tools that can help to make better sive first-pass metabolism in both the intestinal wall and the predictions of the in vivo drug product performance (20). liver, mainly mediated by CYP3A4 (28–30). When formulated One of the key biopharmaceutical factors defining oral drug as a once a day (MR) OROS® formulation, the relative absorption are formulation characteristics. In a recent study, we bioavailability of OXY was around 153% compared to its IR investigated the impact that modified/controlled release (MR/ tablet, while the exposure of its main metabolite, N- CR) formulations might have on the oral bioavailability of desethyloxybutynin (DEOB) was reduced by almost 30% (28). substrates of the cytochrome P450 (CYP) 3A4 enzymes using a This reduction in exposure was translated into an improved prospective PBPK modelling and simulation (M&S) approach safety profile due to a reduction in the incidence of dry mouth (21). By employing this approach, we were able to evaluate the episodes, OXY’s main side-effect, which is mainly attributed to interplay between drug and physiological-related factors its active metabolite, yet keeping the same efficacy (31,32). governing intestinal absorption and first-pass metabolism, and in In this study, OXY’s bioavailability differences were inves- particular to identify the possible scenarios where MR formula- tigated by means of a PBPK modelling and simulation approach, tions of a CYP3A substrate might display higher relative combining in vivo, in vitro and in silico data together with an bioavailability (F ) compared to its immediate
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