Year: 2026
Type: article
Abstract: 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 (AUC 0‐ta ) was defined as the AUC targeting the rapid absorption phase that better reflects therapeutic onset with ta numerically equal to T max + 1 SD for the reference product. To address high variability in cross‐route studies, the BE acceptance range for geometric mean ratios of AUC 0‐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 C max and AUC 0‐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.
DOI: 10.1002/jcph.70138
Language: English
Subfield: Statistics and Probability
Field: Mathematics
Domain: Physical Sciences
Open Access status: bronze
OpenAlex ID: W7118529332