Estimation of CYP2D6*10 genotypes on citalopram disposition in Chinese subjects by population pharmacokinetic assay

What is known and objectiveThere is great interindividual variability in citalopram (CIT) pharmacokinetics. We attempted to establish a population pharmacokinetic (PPK) model of CIT in Chinese healthy subjects, to evaluate the effect of genetic polymorphism on CIT pharmacokinetics and to compare the PPK and non-compartmental (NCA) assays in the estimation of CIT bioequivalence. MethodsBlood samples of 23 healthy subjects were collected after administration of CIT; plasma concentration of CIT was analysed using LC/MS-MS. CYP2C19 and CYP2D6*10 genotypes were determined. PPK model was established by using nonlinear mixed-effect modelling (NONMEM). The model was evaluated using goodness-of-fit plots and relative error measurements. Bioequivalence of CIT was evaluated by both PPK and NCA method. Results and discussionThe estimated population absorption rate constant (k(a)), clearance (CL/F) and volume of distribution (Vd/F) in Chinese healthy subjects are 0.64L/h, 12.7L/h and 705L, respectively. Different CYP2C19 and CYP2D6 genotypes have impacts on CIT pharmacokinetics. There is about 5.5% decrement of CL/F for each CYP2C19*2 or CYP2D6*10 allele. The 90% confidence interval of CIT bioavailability obtained from NCA and PPK model were 96.4-105.4% and 92.5-103.4%, respectively. What is new and conclusionThe PPK of CIT is best characterized by a one-compartment disposition model with first-order absorption. CYP2C19 and CYP2D6 genotypes have impacts on the CL/F of CIT. Bioequivalence of CIT can be estimated by both NCA and PPK model.