Bioequivalence of Clozapine Tablet in Thai Schizophrenic Patients

Abstract

Background: Clozapine is an atypical antipsychotic drug that has been used world wide for the treatment of schizophrenic patients. Several generic formulations of this drug are now available.  In order to assure about the efficacy and safety of the generic formulation, it is necessary to compare the bioavailability between the generic and the reference formulations after administration to the patients.

Purpose: To compare the bioavailabilty of two clozapine formulations, Clozapin^Ò (Pharmasant Laboratories Co., Ltd., Thailand) and Clozaril^Ò (Novartis Pharmaceuticals, UK) when administered to schizophrenic patients in the dose of 100 mg every 12 hr until the drug reach steady state.

Study design : Multiple dose steady state, randomized crossover study under non-fasting condition.  The study was approved by the Ethics Review Board of the Khon Kaen University and the Food and Drug Administration, Ministry of Public Health.

Subject : 18 Male Thai schizophrenic patients

Methods: The subjects received 100 mg of either the Clozapin^Ò or Clozaril^Ò per oral bid for 7 days. At day 7 of each study phase, the drug levels were reached the steady state/  Two hour after meal, the drug was administered and  blood samples were collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 hr. Plasma was separated and stored at –80^oC until assay. The plasma concentration of clozapine was determined by high performance liquid chromatography. Pharmacokinetic parameters were calculated from the plasma-concentration time profiles. The bioequivalence between the two formulations was assessed from the peak plasma concentrations (C_max) and area under the concentration-time curve (AUC_0-12 ) ratios.

Results: All subjects well tolerated both clozapine formulations. No serious adverse effects were reported. The T_max, terminal half-life and the total plasma clearance of clozapine observed in the present study were comparable to those observed in other previous reports. All of the evaluated pharmacokinetic parameters between the Test and Reference formulations were of comparable. The 90% confident interval for the ratio of means for the LnC_max (0.9453-1.1182) and LnAUC_0-12 (0.9734-1.0889) are within the guideline range of bioequivalence (0.80 to 1.25).

Conclusion: The result demonstrated that the Test formulation, Clozapin^Ò was bioequivalent to the Reference formulation, Clozaril^Òwhen orally administered in multiple –dose to schizophrenic patients.