Andrés Olivares-Morales (1), Michael Gertz (1), Leon Aarons (2) and Amin Rostami-Hodjegan (2,3)
(1)Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel. (2) Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, UK. (3) Certara, Blades Enterprise Centre, Sheffield, UK.
Objectives: A recently published absorption physiologically-based pharmacokinetic (PBPK) model was used and applied to mechanistically predict the oral bioavailability differences observed for oxybutynin’s (OXY) OROS formulation compared to its immediate release (IR) tablet [1]. The PBPK model predictions suggested that the higher bioavailability observed for the OROS formulation was due to a reduced CYP3A-mediated intestinal metabolism. This highlighted the fact that while the distal absorption from the OROS formulation significantly reduced OXY’s fraction absorbed (fa), the decreased abundance of CYP3A enzymes in the distal gastrointestinal tract led to a “bypass” of the CYP3A-mediated first-pass metabolism and an increase on the intestinal availability (FG)[1]. The purpose of this work is to explore the implications that the aforementioned formulation-dependent differences in intestinal metabolism can have on drug-drug interactions.
Methods: The PBPK model was expanded to incorporate the different aspects of OXY’s metabolism [2]. This model was then used to investigate the interplay between drug release, CYP3A-mediated metabolism and DDIs using OXY as a model drug. Simulations were conducted assuming different OXY formulations of varying release rates covering IR tablets to extended release (ER) formulations (24 h release). The ketoconazole plasma, hepatic and intestinal concentration profiles were simulated in SimCYP v14 using the default ketoconazole model within SimCYP, whereas for the DDI simulations the profiles were combined with the mechanistic model developed for OXY in Matlab 2016a. For each formulation a DDI study was simulated in the presence of a strong CYP3A4 inhibitor (ketoconazole). The ratios (with and without interaction) of AUC, oral bioavailability (F), hepatic availability (FH) and FG were then evaluated for each formulation.
Results: The simulations demonstrated that a variation of the release rate from rapid to extended release can reduce the DDI magnitude in the presence of a strong CYP3A4 inhibitor by reducing the fold change in the AUC, from 4.5 fold to almost 2 fold. These results are in line with what has been reported previously for OXY where a change in formulation from IR to OROS reduced the AUC ratio from 3-4 to 2 fold in the presence of ketoconazole [3]. A similar trend was observed for the bioavailability ratio (F ratio), where a decrease was observed by switching from IR to ER formulations, from 2.8 to 1.2 fold. Given that the FH ratio remained relatively constant between formulations and that the changes in FG ratio were in line with those of oral bioavailability, this suggests that the decrease in the AUC ratio was mainly due to changes in the intestinal first pass between formulations.
Conclusions: This example highlights the importance that formulations can have when evaluating clinically-relevant DDI involving CYP3A substrates. In addition, given that only the FG ratios were affected by the change in formulation, this approach can be useful to gain information regarding a compound’s FG when IV data is not available. Nevertheless, extended work needs to be conducted to validate this hypothesis.
References:
[1] Olivares-Morales A, Ghosh A, Aarons L, Rostami-Hodjegan A. Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS(R) Formulation of Oxybutynin. The AAPS Journal. 2016;18(6):1532-49. doi: 10.1208/s12248-016-9965-3.
[2] Olivares-Morales A, Ghosh A, Aarons L, Rostami-Hodjegan. Combining population with physiologically-based pharmacokinetic (PBPK) models for oral drug absorption: Predicting the segmental bioavailability differences of R-oxybutynin and its main metabolite using a middle out approach; Page 25 (2016) Abstr 5825 [www.page-meeting.org/?abstract=5825]
[3] U.S. Food and Drug Administration. Ditropan XL® Product Label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/17577se8-033,18211se8-016,20897slr010_ditropan_lbl.pdf: U.S. Food and Drug Administration,; 2015 [cited 2015 06/01/2015]; Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/17577se8-033,18211se8-016,20897slr010_ditropan_lbl.pdf.
Reference: PAGE 27 (2018) Abstr 8707 [www.page-meeting.org/?abstract=8707]
Poster: Drug/Disease Modelling - Absorption & PBPK