Journal of Bioequivalence & Bioavailability

P-gp mediated DDI prediction by Simcyp modeling: Systematic literature review and a case study

7^th World Congress on Bioavailability & Bioequivalence: BA/BE Studies Summit

August 29-31, 2016 Atlanta, USA

Di Bei, Jin Zhang, Haiying Sun and Xuemin Jiang

University of Florida, USA
Novartis Institutes for BioMedical Research, USA

Posters & Accepted Abstracts: J Bioequiv Availab

Abstract:

P-gp mediated drug-drug interaction (DDI) has been a challenge for accurate prediction in clinical. Complex in-vitro to invivo extrapolation (IVIVE) occurs when the perpetrator concurrently inhibits on both metabolizing enzyme and transporter. Therefore, physiologically-based pharmacokinetic (PBPK) model is useful in this case to integrate drug�??s absorption, distribution, metabolism and excretion (ADME) together with human�??s intrinsic and extrinsic factors. In our study, Simcyp (version 13) with the advanced dissolution, absorption and metabolism (ADAM) module and the full PBPK module was utilized to describe clinical PK and further evaluate p-gp mediated DDI between drug A and drug B. Drug A was a substrate of both CYP3A4 and P-gp while drug B was a TDI of CYP3A4 and a potent inhibitor of p-gp. In vitro measured drug properties, preclinical DDI data and the clinical DDI were incorporated into the model. The rationale of our simulations and optimizations was based on FDA guidance and systemic literature review. 4 models were compared considering the predictability and physiological feasibility. The final model with the optimized p-gp kinetics described the clinical observations reasonably, with the modeled drug A�??s Cmax and AUC ratios at 3.3 and 3.1-fold increase, respectively versus observed Cmax and AUC ratios at 3.3 and 3.1-fold increase in the clinical study. Thus, it was concluded that p-gp kinetics needs to be well characterized in order to improve the predictability of the model. And Clinical DDI data are valuable for PBPK model modification. The bottom-up approach combined with top-down approach can provide helpful insight.

Biography :

Email: db4dc@ufl.e