Population pharmacokinetic modeling of steady state clearance of carbamazepine and its epoxide metabolite from sparse routine clinical data

Objective: To develop a population pharmacokinetic model to evaluate the effects of variety of covariates on clearance of carbamazepine (CBZ) and its main metabolite carbamazepine-10,11-epoxide (CBZE) in Chinese population. Methods: Serum samples at steady trough state (n = 459) were collected prospectively from 408 compliant outpatients during their routine clinical care. CBZ and CBZE concentrations were simultaneously determined by high performance liquid chromatography. Population clearance (CL) of CBZ and CBZE were estimated by non-linear mixed effect modeling and NONMEM program with a one-compartment model of first-order absorption and elimination. Results: Total body weight (TBW), dose and concomitant medication were all important determinants of CL of CBZ and CBZE. The final regression model for CBZ was: CL(CL/F)(L/H)=0.141xDose(mg/d)(0.406) xTBW(kg)(0.117) x 1.23(VFA) x 1.44(PHT) x 1.26(FB) Vd(CL/F)(L)=72.0 where VPA = 1 for patients comedicated with valproic acid and its dose greater than 18 mg/kg, otherwise VPA = 0; PHT = 1 for patients comedicated with phenytoin, otherwise PHT = 0; PB = 1 for patients comedicated with phenytoin, otherwise PB = 0. The final regression CL model for the CBZE was: CL(CL/F)(L/h)=0.686xDose(mg/d)(0.311) (VPA) xTBW(kg)(0.440)x0.693 Vd(CL/F)(L)=175 where VPA = 1 for patients comedicated with valproic acid, otherwise VPA = 0. Conclusion: The current models, which describe CL of CBZ and CBZE in terms of patient specific details, can be used as a reference to optimize CBZ therapy in Chinese epilepsy patients.