Application of Physiologically-Based Pharmacokinetic Modeling to Predict Gastric pH-Dependent Drug-Drug Interactions for Weak Base Drugs.

ABSTRACT: Weak-base drugs are susceptible to drug-drug interactions (DDIs) when coadministered with gastric acid-reducing agents (ARAs). We developed PBPK models to evaluate the potential of such pH-dependent DDIs for four weak-base drugs, i.e., tapentadol, darunavir, erlotinib, and saxagliptin. The physiologically-based pharmacokinetic (PBPK) models of these drugs were first optimized using pharmacokinetic (PK) data following oral administration without ARAs, which were then verified with data from additional PK studies in the presence and absence of food. The models were subsequently used to predict the extent of DDIs with ARA coadministration. Sensitivity analysis was conducted to explore the impact of gastric pH on quantitative prediction of drug exposure in the presence of ARA. The results sugg

SUBMITTER: Dong Z 

PROVIDER: S-EPMC7438815 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature