Clinical relevance of bioequivalence acceptance criteria. The example of terbinafine.

Objective: The present study was conducted with the aim of investigating which acceptance criteria for bioequivalence are relevant for orally applied antimycotics using terbinafine (CAS 78628-80-5) as an example.

Methods: A bioequivalence trial was performed in 18 healthy male volunteers with the aim of comparing a new generic product (tablets containing terbinafine hydrochloride, equivalent to 250 mg base) with the originator product. The trial was performed according to an open, cross-over design in one study centre. In each of the two study periods (separated by a wash-out of 14 days) a single dose of one 250 mg tablet (test or reference) was administered. Blood samples were taken up to 72 h post dose, the plasma was separated and the concentrations of terbinafine were determined by a liquid chromatography-mass spectrometry (LC-MS-MS) method with a quantification limit of 14 ng/ml. AUC0-infinity, AUC0-tlast, Cmax and tmax were calculated for both formulations and compared according to the currently valid CPMP Note for Guidance for the evaluation of Bioavailability and Bioequivalence.

Results: The parametric 90% confidence intervals for the primary target parameters were between 0.89 and 1.09 AUC0-tlast and between 0.71 and 0.95 for Cmax. The acceptance ranges prospectively defined in the protocol for this trial were fulfilled. In the light of the currently valid CPMP Note for Guidance, the question still arose whether the overall positive bioequivalence statement was clinically feasible. Taking into account the mechanism of action and the available efficacy and safety data on terbinafine, this question was answered positively.

Conclusion: In the case of oral antimycotic agents and especially terbinafine, the bioequivalence acceptance range for Cmax can be expanded to 0.7-1.43, if the acceptance criteria for AUC are fulfilled.