Physiologically Based Pharmacokinetic Model of Venlafaxine Considering CYP2D6 Polymorphisms

Abstract

The aim of this study was to construct a physiologically based pharmacokinetic (PBPK) model based on the Nonlinear Mixed Effect Model (NONMEM) using venlafaxine pharmacokinetic data obtained from human subjects, and to investigate the effect of CYP2D6 polymorphisms with varying hepatic intrinsic clearance (CL_{int, h}). Eight compartments of the human body were considered in our PBPK model. CL_{int, h} was estimated to evaluate the contribution of CYP2D6 polymorphism to the first-pass effect and systematic metabolism of venlafaxine in the PBPK model. The PBPK model was confirmed to be functionally similar to a pharmacokinetic one-compartment model by frequency analysis. In addition, the influence of CL_{int, h} on gain and cut-off frequency was evaluated, because the frequency characteristics reflected the transient response of venlafaxine concentration. The results of CL_{int, h} (CYP2D6^*1/^*1, 259.7 L·hr^-1) and the liver-to-plasma partition coefficient (48.4) suggested that venlafaxine is sufficiently distributed and ultimately metabolized by the liver. Both CL_{int, h} in CYP2D6^*1/^*10 and CYP2D6^*10/^*10 could be estimated as 106 and 51 L·hr^-1, respectively, based on the value of CL_{int, h} in CYP2D6^*1/^*1. We found that there was limited metabolic capacity of CYP2D6^*1/^*10 and CYP2D6^*10/^*10 in the liver compared to that of CYP2D6^*1/^*1. In conclusion, the PBPK model was a useful tool in evaluating the contribution of CYP2D6 polymorphism to the hepatic metabolism of venlafaxine.