(T1330-04-26) Effect of Omeprazole Administration on the Pharmacokinetics of Oral Extended-Release Nifedipine: Physiologically Based Pharmacokinetic Modeling

Purpose: Proton pump inhibitors (PPIs) can affect the release of drugs from their dosage forms in vivo by elevating the gastric pH. Our recent clinical study has demonstrated that drug-drug interactions (DDIs) exist between a PPI, omeprazole, and nifedipine extended-release (ER) formulations, where systemic exposure of nifedipine was increased in subjects after multiple-dose pretreatment of omeprazole¹. However, the mechanism of the observed DDIs between omeprazole and nifedipine has not been well understood, as the DDI may also be mediated through CYP3A4 enzyme inhibition in addition to the elevated gastric pH caused by omeprazole. This study used physiologically-based pharmacokinetic (PBPK) modeling to understand the effect of omeprazole on nifedipine PK while dosing with two nifedipine ER formulations (pH-dependent and pH-independent release).

Methods: The PBPK models for omeprazole and nifedipine were constructed using a population-based absorption, distribution, metabolism and excretion PBPK platform (V17R1; Certara, Sheffield, UK). These models were verified using clinical omeprazole and nifedipine (immediate-release) DDI data². The PKs of nifedipine from ER formulations in the presence of multiple dose (MD) omeprazole were predicted using the verified PBPK models together with in vitro nifedipine ER dissolution profiles under various pHs. The prediction results were compared to the data from a crossover clinical study of nifedipine ER products (single dose) and omeprazole (MD).

Results: The PBPK modeling and simulation showed that inhibition of CYP3A4 enzyme activity, but not increased gastric pH in the presence of omeprazole, significantly increased nifedipine C_max and AUC in both pH-independent and pH-dependent ER formulations (See Table 1).

Conclusion: The data obtained from this study suggest that the impact of elevated gastric pH on nifedipine PK was minimal after multidose of omeprazole pretreatment. In contrast, the statistically significant nifedipine exposure increase observed may largely be accounted for by CYP3A4-mediated DDIs between omeprazole and nifedipine.

References: 1. Zhao, L. et al. Effect of omeprazole administration on the pharmacokinetics of oral extended-release nifedipine: clinical study. Under consideration for publication after revision submitted (2023).
2. Le Merdy, M. et al. Physiologically based pharmacokinetic modeling approach to identify the drug-drug interaction mechanism of nifedipine and a proton pump inhibitor, omeprazole. Eur J Drug Metab Pharmacokinet 46, 41-51 (2021).