POPULATION PHARMACOKINETICS OF CLOZAPINE EVALUATED WITH THE NONPARAMETRIC MAXIMUM-LIKELIHOOD METHOD

Aims To evaluate the distribution of population kinetic parameters for clozapine and their relationship to age and gender in patients on con tinuous treatment with the drug. Methods Retrospective therapeutic dru g monitoring data (391 samples from 241 patients) were evaluated using the nonparametric maximum Likelihood method. Patients treated concomi tantly with drugs known to interact with clozapine were not included. The distribution of clozapine clearance was compared with the distribu tion of the activity of the drug metabolic enzyme CYP1A2 found in othe r populations, as recent studies indicate that CYP1A2 is a major deter minant for clozapine elimination. The kinetic linearity for clozapine was studied in 41 patients who each provided data from more than one d ose level. Results Clozapine clearance was highly variable in the popu lation and skewed towards high values. Men had higher clearances CL/F; median with 25% and 75% quartiles 38.2 (22.0, 60.0) vs 28.3 (15.2, 48. 6) 1 h(-1)) and a larger volume of distribution V/F (694 (224, 970) vs 401 (189, 932) 1) than women. Clearance did not decrease with age in any gender. Clozapine clearance was similarly distributed as the indic es of CYP1A2-activity found in other populations by other authors. Evi dence of nonlinear kinetics was not found. Conclusion The large kineti c variability for clozapine found in this study implies that the dose of clozapine needs to be individualised over a wide dose range. The si milarity of the distribution of clozapine clearance in this study and the CYP1A2-activity in other populations support the assumption that C YP1A2 is a major determinant for clozapine elimination.