Parent drug and/or metabolite? Which of them is most appropriate to establish bioequivalence of two oral oxcarbazepine formulations in healthy volunteers?
The bioequivalence of two 600-mg oxcarbazepine oral formulations (Aurene, Ivax Argentina, [test]; and Trileptal, Novartis Laboratories, [reference]) were assessed through the simultaneous determination of oxcarbazepine and the active metabolite 10,11-dyhydro-10-hydroxy-carbamazepine derivative (MHD). 12 healthy male volunteers received a single oral dose of 600 mg of each formulation, in a balanced, randomized, paired, crossover design, with a 7-day wash out period. Oxcarbazepine and MHD concentrations were established at 0.5,1, 1.5, 2, 3, 4, 6, 8, 24 and 48 h post dose by high performance liquid chromatography (HPLC). The regression coefficient determined for oxcarbazepine calibration curves was 0.9933 +/- 0.0236; and for MHD, was 0.9897 +/- 0.0017. The working range for both oxcarbazepine and its metabolite was from 0.1 to 10.0 microg/ml. The quantification limit was 0.1 microg/ml. The 90% confidence interval (CI) geometric mean for oxcarbazepine C(max), AUC(0-48 h) and AUC(0-infinity) ratios (test : reference) were 74.1-146.2%, 85.6-171.5% and 89.6-169.8%, respectively, and the 90% CI geometric mean for MHD C(max), AUC(0-48 h) and AUC(0-infinity) ratios (test : reference) were 84.0-122.3, 93.2-117.9 and 96.5-116.7, respectively. These results established the bioequivalence of two oxcarbazepine formulations from MHD kinetic data used in 12 healthy volunteers, while it was not possible to establish bioequivalence with oxcarbazepine. MHD quantification is preferred to that of the oxcarbazepine in order to assess bioequivalence, as the metabolite is responsible for the antiepileptic activity, presents linear kinetics in the therapeutic range, has lower intra-individual variability and higher plasma levels and half life than the parent drug.
Department of Pharmacology, School of Medicine, Paraguay 2215, Piso 16, CP: ZC1845, Ciudad Autónoma de Buenos Aires, Argentina-Universidad de Buenos Aires, Argentina. gdigirolamo@arnet.com.ar
Guillermo
G
Di Girolamo
Javier A W
JA
Opezzo
Daniel
D
Schere
Claudio D
CD
Gonzalez
Juan J Rodriguez
JJ
Moncalvo
D000284:Administration, Oral; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D002138:Calibration; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid / Q000592:standards; D018592:Cross-Over Studies; D006207:Half-Life; D006801:Humans; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D000078330:Oxcarbazepine; D012016:Reference Values; D015203:Reproducibility of Results; D012107:Research Design; D013810:Therapeutic Equivalency
C039775:10,11-dihydro-10-hydroxycarbamazepine; D000927:Anticonvulsants; D002220:Carbamazepine; D000078330:Oxcarbazepine