Steady-state bioequivalence study of clozapine tablet in schizophrenic patients.
OBJECTIVE
To compare the bioavailability of two clozapine formulations (100 mg Clozaril tablet from Novartis Pharmaceuticals UK Ltd., UK, as a Reference formulation and 100 mg Cloril tablet from Atlantic Laboratories Corp., Ltd., Thailand, as a Test formulation). The present study was conducted under real-life conditions in schizophrenic patients using a steady-state, multiple-dose, randomized crossover design to avoid the risk of adverse effects in healthy volunteers and pharmacokinetic difference between single and multiple-dose of the drug.


METHODS
The subjects received 100 mg bid of either the Reference formulation or the Test formulation for 7 days. At day-7 of each study phase, blood samples were collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h after drug administration. Plasma was separated and stored at -80 degrees C until assay. The plasma concentration of clozapine was determined by high performance liquid chromatography. Pharmacokinetic parameters were calculated from the observed plasma-concentration time profiles. The bioequivalence between the two formulations was assessed by calculating individual peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC(0-12 h)) ratios.


RESULTS
All subjects well tolerated both clozapine formulations. No serious side effects were reported. The Tmax, terminal half-life and the total plasma clearance of clozapine (uncorrected for bioavailability) observed in the present study were comparable to those observed in other previous reports. All of the pharmacokinetic parameters investigated in the present study calculated from the subjects after administration of Test and Reference formulations were close. The 90% confident interval for the ratio of means for the lnCmax (0.9784-1.0622) and lnAUC(0-12h) (0.9559-1.0441) are within the guideline range of bioequivalence (0.80 to 1.25).


CONCLUSIONS
The result demonstrated that the Test formulation was bioequivalent to the Reference formulation (Clozaril) when orally administered in schizophrenic patients, in terms of both the rate and extent of absorption.
Tassaneeyakul
Wongwiwat
W
Department of Toxicology, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand.
Kittiwattanagul
Khanogwan
K
Vannaprasaht
Suda
S
Kampan
Jureeporn
J
Tawalee
Arporn
A
Puapairoj
Prapawadee
P
Tiamkao
Siriporn
S
Juthagridsada
Srisaard
S
Kukongviriyapan
Veerapol
V
Tassaneeyakul
Wichittra
W
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D002626:Chemistry, Pharmaceutical; D003024:Clozapine / Q000097:blood* / Q000627:therapeutic use*; D018592:Cross-Over Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia / Q000097:blood* / Q000188:drug therapy*; D013607:Tablets; D013810:Therapeutic Equivalency
D013607:Tablets; D003024:Clozapine