Virtual internal exposures of lansoprazole administered to cytochrome P450 2C19 poor metabolizers estimated by simplified physiologically based pharmacokinetic modeling.

Abstract

Although the importance of polymorphic cytochrome P450 2C19 (CYP2C19) in the metabolism of proton pump inhibitors is well recognized, genotyping patients for CYP2C19 before prescribing proton pump inhibitors is not currently recommended in some Asian countries. Adverse events in patients prescribed 30-mg lansoprazole alone have been reported in the Japanese Adverse Drug Event Report database. This study aimed to evaluate virtual internal exposure to lansoprazole in CYP2C19 poor metabolizers using a simplified physiologically based pharmacokinetic (PBPK) model. The input parameters for the simplified PBPK model were based on reported plasma concentrations for 30-mg lansoprazole. For poor metabolizers, the in vivo hepatic intrinsic clearance value was reduced from 13.4 L/hr to 3.4 L/hr. For comparison, a population-based (full) model was used based on the incorporated parameters for lansoprazole (latest Simcyp Simulator version 25). High virtual plasma and hepatic maximum concentrations and the areas under the concentration-time curves of lansoprazole in the poor metabolizers were generated by the simplified and full PBPK models. These results suggest that virtual internal exposure to lansoprazole in CYP2C19 poor metabolizers can be evaluated using PBPK modeling systems. Despite the limited references to CYP2C19 polymorphisms in current Asian drug labeling, such in silico information could be informative.