Open-Label Crossover Oral Bioequivalence Pharmacokinetics Comparison of a Single Dose of Super-bioavailable Itraconazole 130 mg and Innovator SUBA®-Itraconazole Capsules 130 mg (2 x 65 mg) in Healthy Adults Under Fed Conditions

Abstract

Introduction: Itraconazole (ITZ), an antifungal agent taken orally, demonstrates intricate and variable absorption kinetics, significantly impacted by food intake. The invention of Super-Bioavailable Itraconazole (SITZ) has led to a surge in various brands offering different dosages of SB ITZ, overcoming barriers associated with conventional itraconazole. Hence, this study was planned to evaluate the bioequivalence of Itraconazole Capsules 130 mg (Test) of Glenmark Pharmaceuticals Ltd, India, with Innovator SITZ 130 mg (2× 65 mg; Reference) in healthy, adult, male, human subjects under fed condition in addition to safety and tolerability. Materials and methods: A total of 36 subjects were enrolled in an open-label, balanced, randomized, two-treatment, two-sequence, two-period, two-way crossover, single dose oral bioavailability study which was conducted in healthy, adult, human male subjects under fed conditions. Test and reference product were administered sequentially. 22 blood samples per subject were collected as pre and post dose within 2 hours of intake of food. The concentrations of ITZ and Hydroxy-itraconazole (OH-ITZ) in plasma were measured by High-Performance Liquid Chromatography-Tandem Mass Spectrometry (HPLC-MS/MS). Assessment of bioequivalence was done on the basis of the 90% CIs of the differences of least squares treatment means for Ln-transformed Cmax and AUC0-t of ITZ obtained after single-dose administration under fed conditions for Test (T) vs Reference (R) Results: The mean value of the area under curve (AUC0-t) of test drug (SITZ 130 mg) was 4604.98 ng.hr/mL whereas for reference drug (SITZ, 2 x 65 mg), it was 4812.04 ng.hr/mL which was statistically non-significant. The Pharmacokinetic parameters for OH-ITZ measured from both formulations followed a pattern in terms of bioavailability similar to that for the ITZ plasma blood levels for the test/reference ratios for Cmax (100.88%) and AUC0-t (97.44%). Subjects crossed over from one period of administration of either test or reference drugs to a second period with dosing with the opposite drug attained higher Cmax and AUC0-t values for ITZ, than the same subjects administered reference drug in this study. The administration of both the drugs were well tolerated by all the subjects with no added adverse events Conclusion: The pharmacokinetics activity was found to be comparable and bioequivalent between test product at 130 mg dose and innovator itraconazole 130 mg (2x 65 mg). Also, both the drugs were found to be safe and well tolerated with no adverse effects.