Estimation of CYP2 D6*10 genotypes on citalopram disposition in Chinese subjects by population pharmacokinetic assay.

What is known and objective There 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. Methods Blood samples of 23 healthy subjects were collected after administration of CIT; plasma concentration of CIT was analysed using LC/ MS- MS. CYP2 C19 and CYP2 D6*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 discussion The estimated population absorption rate constant ( k_a), clearance ( CL/ F) and volume of distribution (Vd/F) in Chinese healthy subjects are 0.64 L/h, 12.7 L/h and 705 L, respectively. Different CYP2 C19 and CYP2 D6 genotypes have impacts on CIT pharmacokinetics. There is about 5.5% decrement of CL/ F for each CYP2 C19*2 or CYP2 D6*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 conclusion The PPK of CIT is best characterized by a one-compartment disposition model with first-order absorption. CYP2 C19 and CYP2 D6 genotypes have impacts on the CL/F of CIT. Bioequivalence of CIT can be estimated by both NCA and PPK model. [ABSTRACT FROM AUTHOR]