Semi-physiological Pharmacokinetic Model of Clozapine and Norclozapine in Healthy, Non-smoking Volunteers: The Impact of Race and Genetics.

ABSTRACT

BACKGROUND AND OBJECTIVES: Clozapine is the medication of choice for treatment-resistant schizophrenia. However, it has a complex metabolism and unexplained interindividual variability. The current work aims to develop a pharmacokinetic model of clozapine and norclozapine in non-smokers and assess the impact of demographic and genetic predictors. METHODS: Healthy volunteers were recruited in a population pharmacokinetic study. Blood samples were collected at 30 min and 1, 2, 3, 5 and 8 h following a single flat dose of clozapine (12.5 mg). The clozapine and norclozapine concentrations were measured via high-performance liquid chromatography-ultraviolet method. A semi-physiological pharmacokinetic model of clozapine and norclozapine was developed using nonlinear mixed-effects modeling. Clinical and genetic predictors were evaluated, including CYP1A2 (rs762551) and ABCB1 (rs2032582), using restriction fragment length polymorphism. RESULTS: A total of 270 samples were collected from 33 participants. The data were best described using a two-compartment model for clozapine and a two-compartment model for norclozapine with first-order absorption and elimination and pre-systemic metabolism. The estimated (relative standard error) clearance of clozapine and norclozapine were 27 L h-1 (31.5 %) and 19.6 L h-1 (30%), respectively. Clozapine clearance was lower in sub-Saharan Africans (n = 4) and higher in Caucasians (n = 9) than Asians (n = 20). Participants with CYP1A2 (rs762551) (n = 18) and ABCB1 (rs2032582) (n = 12) mutant alleles had lower clozapine clearance in the univariate analysis. CONCLUSIONS: This is the first study to develop a semi-physiological pharmacokinetic model of clozapine and norclozapine accounting for the pre-systemic metabolism. Asians required lower doses of clozapine as compared with Caucasians, while clozapine pharmacokinetics in sub-Saharan Africans should be further investigated in larger trials.