Senior Scientific Advisor Certara UK / Simcyp Sheffield, England, United Kingdom
Physiologically based pharmacokinetic (PBPK) modelling is recognised by the U.S. FDA as an alternative approach to clinical trials for the evaluation of pH-dependent drug-drug interactions (DDIs). To date, such DDIs have predominantly been assessed empirically by setting the stomach pH to match the worst-case scenario. We present here a mechanistic modelling approach encompassing a dynamic gastric acid secretion model, upon which PBPK-pharmacodynamic (PD) gastric pH effect models for proton pump inhibitors and H2-receptor antagonists were developed and verified. Performance verification cases show the ability of the models to successfully capture DDIs mediated by gastric pH. Mechanistic modelling should improve the qualitative and quantitative predictions of pH-dependent DDIs. It is a useful in silico tool to assess the efficacy of DDI mitigation strategies such as dose staggering or formulation changes.
Learning Objectives:
Describe the utility of PBPK-PD gastric pH effect models for proton pump inhibitors and H2-receptor antagonists in the mechanistic prediction of pH-dependent drug-drug interactions.
Discuss the data needed to build a PBPK model.
Discuss the data needed to verify and validate the developed PBPK model.