Development and Evaluation of Physiologically Based Pharmacokinetic (PBPK) Models to Investigate the Effect of CYP2D6 Polymorphism on Metoclopramide Systemic Exposure

Background: Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic tool used to predict how a drug moves through the body by incorporating real human physiology, including organ sizes, blood flows, tissue compositions, and enzyme activities. It has been widely employed to estimate drug exposure in different populations with organ impairment, genotype variabilities, and physiological variations. Metoclopramide is an antiemetic and prokinetic agent that is subject to CYP2D6 polymorphism. The study aims to develop PBPK models for several CYP2D6 variants to predict changes in the pharmacokinetic (PK) behavior of metoclopramide. Methods: To conduct this study, a literature review was conducted, and the retrieved physicochemical, biochemical, and PK data were integrated into PK-Sim to develop a PBPK model. Initially, a non-genotype-specific model was developed and extrapolated to genotype-based models. The models were verified using a Visual Predicted Check (VPC), mean predicted-to-observed ratio (Rpre/obs) values, and mean relative deviation (MRD). Results: The simulated profiles were aligned with the reported data, and all the predicted and observed PK parameters were comparable, as the Rpre/obs values were within the 0.5–2 range and MRD values were