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

Abstract

Comparisons of maximum drug concentration (C_max) and total area under the concentration vs. time curve (AUC) may be inadequate for bioavailability (BA)/bioequivalence (BE) assessments in cases where the shape of the pharmacokinetic (PK) profile of a drug impacts the clinical performance. In such cases, partial area under the concentration vs. time curve (pAUC) has been recommended by regulatory agencies to support BA or BE assessments as a measure of drug exposure over specified time intervals of clinical relevance. This white paper serves as an update to the previously published white paper by Fang et al. at the US Food and Drug Administration (FDA), which introduced the general framework to provide pAUC recommendations. Since August 2020, 18 product-specific guidances (PSGs) have been published or revised using the general framework to provide consistent, science- and risk-based pAUC recommendations. Notable regulatory examples of pAUC applications discussed include loxapine inhalation powder, leuprolide long-acting injectables (LAIs), and goserelin LAIs. This paper discusses recent applications of pAUC in the United States, highlights key examples of pAUC recommendations for regulatory applications, and provides insights about areas for global harmonization of pAUC recommendations.