A KINETIC-MODEL FOR SIMULTANEOUS FIT OF CLOZAPINE AND NORCLOZAPINE CONCENTRATIONS IN CHRONIC-SCHIZOPHRENIC PATIENTS DURING LONG-TERM TREATMENT

Objective: The pharmacokinetic profiles of clozapine and its main meta bolite, norclozapine, were investigated in 18 chronic schizophrenic in patients during long-term treatment. Patients: Patients received stabl e daily doses (between 300 and 900 mg) for at least 1 month. Plasma dr ug concentrations were determined by high performance liquid chromatog raphy. The pharmacokinetic parameters were calculated from both noncom partmental and compartmental approaches with zero-order input rate usi ng a kinetic model for simultaneous fit of clozapine and norclozapine (active metabolite) concentrations. Results: Large interpatient variat ions in pharmacokinetic parameters of the two drugs were observed. Pla sma clozapine concentration peaked on average at 2 hours. The mean eli mination rate constants from compartments 1 (k(10)) and 2 (k(20), elim ination rate constant of norclozapine) were 0.087 and 0.156h(-1), resp ectively. The rate of formation of norclozapine, k(12), averaged 1.25h (-1). The mean fraction of the administered dose converted to norcloza pine was estimated to be 66%. The apparent clearance of clozapine (CL/ F) averaged 44.7 L/h and the volume of distribution (V-c/F) was 7.00 L /kg. The pharmacokinetics of clozapine after multiple doses were linea r over the range of clozapine plasma concentrations of 145 to 1411 mu g/L.. Conclusion: This is the first study assessing the pharmacokineti c profile of clozapine plus norclozapine in plasma during long-term tr eatment. This pharmacokinetic model can be used to determine the popul ation pharmacokinetic parameters of clozapine and norclozapine in orde r to optimise individual dosage regimens using a Bayesian methodology.