Exploring the Impact of CYP1A2 on Carbamazepine Population Pharmacokinetics Using NONMEM Approach

OBJECTIVE To investigate the impact of CYP1A2 on the population pharmacokinetics of carbamazepine in Chinese epileptic children by means of the nonlinear mixed-effects approach. METHODS A total of 720 carbamazepine blood monitoring data and their clinical data were collected retrospectively from 180 children with epilepsy. The population pharmacokinetics were estimated by Phoenix NLME software and the model was conducted. Internal model validation by goodness-of-fit plots and visual predictive check were performed. RESULTS One compartment model with first-order absorption was used to describe the in vivo behavior of carbamazepine. The final model parameters were as follows:CL=3.25×(WT/29.8)^0.22×e^0.05(AA=1)×e^ηCL(L·h^-1), V_d=34.78×e^ηVd(L), K_a=1.2·h^-1. Where AA=1 if CYP1A2-163 was AA, and AA=0 if CYP1A2-163 was CA or CC. The drug clearance nonlinearly increases as the epileptic children gain weight and the CYP1A2-163C>A mutation could accelerate the metabolism of carbamazepine. CONCLUSION The body weight and CYP1A2 polymorphisms were associated with the CL. It is recommended to consider the patient's weight and CYP1A2 genotype before taking carbamazepine.