A 2024 Update on US FDA Implementation of Partial Area Under the Curve Into Bioavailability and Bioequivalence...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Regulatory Science
• Pharmaceutical Development

Background:

• Traditional bioavailability (BA) and bioequivalence (BE) assessments using maximum drug concentration (Cmax) and total area under the curve (AUC) may not fully capture clinical performance for all drug profiles.
• The shape of a drug's pharmacokinetic (PK) profile can significantly influence its clinical efficacy and safety, necessitating more nuanced assessment methods.

Purpose of the Study:

• To provide an updated framework for partial area under the concentration vs. time curve (pAUC) recommendations, building upon previous work by Fang et al. at the FDA.
• To discuss recent regulatory applications of pAUC in the United States, supporting BA/BE assessments for specific drug products.
• To highlight key examples of pAUC recommendations and explore opportunities for global harmonization of these assessments.

Main Methods:

• Review and analysis of regulatory guidances and product-specific guidances (PSGs) utilizing the pAUC framework.
• Case study discussions of pAUC applications for specific drug products, including loxapine inhalation powder and long-acting injectables (LAIs) like leuprolide and goserelin.
• Examination of recent trends and challenges in pAUC implementation and global regulatory alignment.

Main Results:

• Since August 2020, 18 PSGs have been published or revised using the general pAUC framework, ensuring consistent, science-, and risk-based recommendations.
• Successful regulatory applications of pAUC have been demonstrated for diverse formulations, including inhalation powders and LAIs.
• The paper identifies areas where global harmonization of pAUC recommendations is needed to streamline drug development and regulatory review.

Conclusions:

• Partial area under the curve (pAUC) is a valuable tool for BA/BE assessments, particularly when pharmacokinetic profile shapes are critical for clinical performance.
• The updated framework and recent US regulatory applications demonstrate the practical utility and growing acceptance of pAUC.
• Further global harmonization efforts are essential to standardize pAUC recommendations and facilitate international drug approvals.