Bioequivalence Assessment for Intranasal Rapid-Acting Drug Products.

Bioequivalence assessment is critical for generic drug approval, but conventional bioequivalent criteria for identical formulations and routes may not be suitable for cross-route comparisons, especially for rapid-acting drugs. Intranasal formulations provide faster absorption and onset of action compared with oral products. At present, establishing bioequivalence across these routes remains challenging. This study proposes a novel method using partial AUCs. Partial AUC (AUC0-ta) was defined as the AUC targeting the rapid absorption phase that better reflects therapeutic onset with ta numerically equal to Tmax + 1 SD for the reference product. To address high variability in cross-route studies, the BE acceptance range for geometric mean ratios of AUC0-ta was widened to 70%-143%. To evaluate this approach, plasma concentration data from two crossover studies comparing intranasal vardenafil (5 and 3.8 mg) with an approved oral tablet (10 mg) were analyzed. Intra- and inter-subject variabilities were estimated. Initial results indicated that bioequivalence could not be demonstrated due to high variability. However, the simulation with optimized dose selection and increased sample size (e.g., 48 subjects) shows that the 90% confidence intervals for both Cmax and AUC0-ta fell within the expanded bioequivalent limits. In contrast, total AUC failed to meet BE requirements, underscoring its limited relevance for rapid-onset, cross-route comparisons. This adapted BE approach may offer a more suitable method for intranasal and other rapid-acting products. With further validation, it could support regulatory approval and improve patient access to fast-acting therapies.

Duke Scholars

Author Shein-Chung Chow Biostatistics & Bioinformatics, Division of Biostatistics