Evidence from a population pharmacokinetics analysis for a major effect of CYP1A2 activity on inter- and intraindividual variations of clozapine clearance

Interindividual variations of clozapine clearance could be related to individual CYP1A2 activity. A population approach was used to investigate clozapine pharmacokinetics of multiple doses of clozapine in patients. Clozapine plasma concentrations were obtained in 23 patients from therapeutic drug monitoring (83 samples). CYP1A2 activity was estimated by the norclozapine/clozapine plasma levels ratio and data were processed by a nonlinear mixed-effect modelling method. Different covariates (age, body weight, height, CYP1A2 activity, daily dose of clozapine) were tested but CYP1A2 activity was the single parameter that improved significantly the predictive model. The best fit was obtained by integration of a linear relationship between clozapine clearance and CYP1A2 activity. The findings suggest that (i) CYP1A2 activity is a major factor that determines clozapine clearance and (ii) the norclozapine/clozapine ratio could constitute a valuable measure of the CYP1A2 activity. This ratio can be simply determined in the context of therapeutic drug monitoring and could explain the inter- and intraindividual variation of clozapine plasma levels. (C) 2002 Elsevier Science Inc. All rights reserved.