Use of physiologically ‐based pharmacokinetic modeling to understand the effect of omeprazole administration on the pharmacokinetics of oral extended‐release nifedipine

This study used physiologically-based pharmacokinetic (PBPK ) modeling and simulations to investigate the underlying mechanism of these complex DDIs. A formulation exhibiting differences in in vitro dissolution across physiological pH range and another formulation where pH does not impact dissolution appreciably (e.g., an osmotic pump) were chosen to charac terize the potential impact of pH. The PBPK models incorporated two-stage in vitro release profiles via US Pharmacopeia 2 apparatus. PBPK simulations suggest that the elevated gastric pH following multiple-dose administration of omeprazole has a minimal effect on nifedipine pharmacokinetics (PKs), whereas CYP3A4-mediated DDI is likely the main driver to the observed change of nifedipine PKs in the presence of omeprazole. Compared to the osmotic formulation, the slightly increased exposure of nifedipine can be accounted for by the enhanced drug release in the pH-dependent formulation. The repo rted model-based approach may be useful in DDI risk assessments, product formulation designs, and bioequivalence evaluations.
Source: CPT: Pharmacometrics and Systems Pharmacology - Category: Drugs & Pharmacology Authors: Tags: ARTICLE Source Type: research