Development and Evaluation of Physiologically Based Pharmacokinetic (PBPK) Models of Metoclopramide Across the Lifespan: Translation from Adults to Infants.

Background: Physiologically based pharmacokinetic (PBPK) modeling is an established approach used in recent years for estimating drug disposition in challenging clinical scenarios where in vivo studies are difficult to perform. Metoclopramide is a benzamide derivative, widely indicated for its antiemetic and prokinetic actions. This study aims to develop a PBPK model for metoclopramide in infants to predict its systemic exposure in this population. Methods: To develop the model, a detailed literature review was conducted, and the required data related to the drug, human physiology, and published clinical studies were retrieved. After that, all information was integrated into the PK-Sim software, and the model was initially developed in adults to create a base; subsequently, it was extrapolated to infants. After successful development, these models were verified visually and numerically using visual predictive checks (VPCs), mean predicted-to-observed ratios (Rpre/obs), average fold error (AFE), and mean relative deviation (MRD). Results: All simulated profiles were consistent with observed data; computed AFE and Rpre/obs for key pharmacokinetic (PK) parameters, including area under the concentration-time curve from 0 to t (AUC0-t), maximum plasma concentration (Cmax), and clearance (CL), fell within an acceptable two-fold error range. Moreover, the MRD values for all profiles were <2, showing promising agreement between the reported and predicted datasets. Conclusions: The current model provides a robust framework to estimate the PK of metoclopramide in infants, which may help with dose individualization in this vulnerable population.