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

ABSTRACT

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.

KEYWORDS:

• Itraconazole
• comparative bioavailability
• generic drugs

Acknowledgments

The authors would like to thank the subjects who participated in the study, and the staff of the clinical research units who carried out the study. Finally, the trial is registered at Medicines and Medical Devices Agency of Republic of Serbia (ALIMS, N° 515-04-01565-14-1).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Viktorija Dragojević-Simić, Aleksandra Kovačević, Vesna Jaćević and Nemanja Rančić were involved in the conception and design of the manuscript. Snežana Djordjević and Vesna Kilibarda were responsible for method validation and the analytical analyses of the human plasma samples. Aleksandra Kovačević, Nemanja Rančić, and Dubravko Bokonjić were involved in the statistical analysis and data interpretation. Momir Mikov revised the manuscript. Vesna Jaćević was responsible for the paper submission. Viktorija Dragojević-Simić was responsible for drafting the paper, revising it critically, and for the final approval of the version to be published. All the authors agreed to be accountable for all aspects of the work.

Additional information

Funding

This paper was not funded.