Abstract

The purpose of the current study was to develop a physiologically-based pharmacokinetic (PBPK) model for dextromethorphan (DEX) and its metabolites in extensive (EM) and poor metabolizers (PM). The model was used to study the influence of dissolution rates on the sensitivity of Cmax and AUC for immediate release (IR) formulations. Simulation of in vitro cellular transwell permeability was used to confirm lysosomal trapping. GastroPlus™ was used to build a mechanistic absorption and PBPK model of DEX. The model simulations were conducted with and without lysosomal trapping. The simulated results matched well with observed data only when lysosomal trapping was included. The model shows that DEX is rapidly absorbed into the enterocytes, but DEX and its metabolites only appear slowly in the portal vein and plasma, presumably due to lysosomal trapping. For this class of drug, the rate of in vitro and in vivo dissolution is not a sensitive factor in determining bioequivalence (BE). This study shows that dissolution and the rate of absorption into the enterocytes are clinically irrelevant for the performance of DEX IR product. An understanding of the entire underlying mechanistic processes of drug disposition is needed to define clinically relevant product specifications for DEX.