Bioequivalence study of two formulations of itraconazole 100 mg capsules in healthy volunteers under fed conditions: a randomized,three-period,reference-replicated,crossover study

Background: The aim of the study was to evaluate the bioequivalence of two itraconazole 100 mg capsule formulations.

Research design and methods: The single-center, open-label, randomized, three-period, three-sequence, reference-replicated, cross-over study included 38 healthy subjects under fed conditions. In each study period (separated by a 14-day washout), a single oral dose of the test (T) or reference (R) product was administered. Blood samples were collected at pre-dose and up to 72.0 h after administration. The calculated pharmacokinetic parameters, based on the plasma concentrations of itraconazole and hydroxy itraconazole, were AUC_0-72h, AUC_0-∝, C_max, T_max, T_1/2 and K_el.

Results: The 90% CI for the test/reference geometric means ratio for the parent compound, itraconazole, was in the range from 85.29% to 116.07% for AUC_0-72h. Since the coefficient of variation (CV) for the reference product was 44.95% for C_max, the 90% CI for this parameter for itraconazole was 93.49–133.78%, which was within the proposed limits of the EMA for bioequivalence of 72.15–138.59%. During the study, 4 subjects encountered a total of 14 mild adverse events.

Conclusions: The use of the reference-scaling approach with 3-period design (TRR, RTR, and RRT) was an efficient way to demonstrate that two commercially available oral itraconazole formulations met the predetermined bioequivalence criteria.