Bioequivalence Assessment for Intranasal Rapid-Acting Drug Products

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Pharmaceutical Sciences
• Regulatory Science

Background:

• Conventional bioequivalence (BE) criteria are inadequate for cross-route comparisons, particularly for rapid-acting drugs like intranasal formulations.
• Intranasal delivery offers faster absorption and onset of action than oral routes, posing challenges for standard BE assessments.
• Establishing robust BE methods for cross-route comparisons is crucial for generic drug approval and patient access.

Purpose of the Study:

• To propose and evaluate a novel bioequivalence assessment method using partial area under the curve (AUC) for cross-route comparisons.
• To investigate the suitability of partial AUC (AUC0-ta) and an expanded acceptance range for evaluating intranasal versus oral formulations.
• To assess the impact of dose optimization and sample size on demonstrating bioequivalence for rapid-acting drugs.

Main Methods:

• Defined partial AUC (AUC0-ta) targeting the rapid absorption phase, with 'ta' set to Tmax + 1 SD of the reference product.
• Expanded the BE acceptance range for geometric mean ratios of AUC0-ta to 70%-143% to accommodate high cross-route variability.
• Analyzed plasma concentration data from crossover studies of intranasal vardenafil versus oral vardenafil, employing simulations with adjusted doses and sample sizes.

Main Results:

• Initial analysis showed failure to demonstrate bioequivalence due to high variability.
• Simulations indicated that with optimized dosing and increased sample size (48 subjects), 90% confidence intervals for Cmax and AUC0-ta fell within the expanded limits.
• Total AUC failed to meet BE requirements, highlighting its limitations for rapid-onset, cross-route comparisons.

Conclusions:

• The proposed partial AUC method with an expanded acceptance range offers a more suitable approach for assessing bioequivalence of intranasal versus oral rapid-acting drugs.
• Simulations suggest that this adapted BE strategy can successfully demonstrate bioequivalence under optimized conditions.
• Further validation of this method could support regulatory approval for intranasal and other fast-acting pharmaceutical products.