Pharmacokinetic Prediction of CYP2D6 Genotypes of Metoclopramide in Adults and Children Using Physiologically Based Pharmacokinetic Modeling

Abstract

Metoclopramide (MCP) is a dopamine D2 antagonist and 5‐HT4 receptor agonist to stimulate gastric contractions for the treatment of Gastroparesis and gastroesophageal reflux disease. It is predominantly metabolized in liver by cytochrome P450 2D6 (CYP2D6). Thus, CYP2D6 genetic polymorphism has essential effects on the pharmacokinetics of metoclopramide and exhibits variability between the different phenotypes. Based on our clinical trials, we developed a physiologically based pharmacokinetic (PBPK) model for CYP2D6 *wt/*wt group and scaled to other CYP2D6 genotypes and pediatric group. A 10 mg single oral dose of metoclopramide was given to forty‐three healthy Korean subjects composed of CYP2D6 *wt/*wt (*wt = *1 or *2, n=12), *wt/*10 (n=8), *10/*10 (n=15) and *5/*10 (n=8) genotypes. The plasma concentrations of metoclopramide were measured using an HPLC‐MS/MS system. Based on data of our clinical trials and physicochemical properties, PBPK model of metoclopramide was built utilizing PK‐sim® software (PK‐Sim® 7.4, Bayer AG, Wuppertal, Germany). After that, a PBPK model has fitted the 99.998% confidence interval criteria (Abduljalil K et al., 2014) and validated by comparing it with other clinical trials. We found meaningful differences in AUCinf, AUCend, oral clearance (CL/F) and Cmax in CYP2D6 genotypes (P<0.0001, respectively). The mean Cmax for the clinical pharmacokinetic data were 26.8 ± 9.2, 37.6 ± 6.4, 44.3 ± 9.2 and 45.7 ± 6.9 in CYP2D6*wt/*wt, *wt/*10, *10/*10 and *5/*10 group, respectively. And the mean Cmax for the simulated pharmacokinetic data were 33.9, 42.5, 41.5 and 45.1 in CYP2D6*wt/*wt, *wt/*10, *10/*10 and *5/*10 group, respectively. According to the developed PBPK model of metoclopramide, the observed pharmacokinetic parameters of adults were all within model acceptance criterion, whereas in those of pediatric excluding CL/F met the acceptance criteria. In this study, we first attempted pharmacokinetics prediction of the CYP2D6 genotype of metoclopramide in adults and children using physiologically based pharmacokinetic modeling. This PBPK model could be applied to personalized therapies to determine the appropriate dosage to minimize adverse effects in patients with functionally impaired CYP2D6 activity. So, this PBPK model will help make more effective and less risky clinical decisions in different CYP2D6 genotypes which will lead to a more successful stomach and esophageal problem management.Observed (circles) and simulated (lines) values of metoclopramide in relation to CYP2D6 genotype in populations. The dashed lines represent the 5th and 95th percentiles of model predicted plasma concentrations.Figure 1Individual values for Cmax (A) and AUC0–24hr (B) of metoclopramide in relation to CYP2D6 genotype groups. The horizontal bars are mean values for each genotype group.Figure 2