Use of Partial Area Under the Curve in Bioavailability or Bioequivalence Assessments: A Regulatory Perspective.

Abstract

Peak drug concentration (Cmax ) and total exposure, such as area under the concentration-time curve (AUC) from time zero to infinity may be insufficient for assessing relative bioavailability (BA) or bioequivalence (BE) among two products in cases where rapid onset of action or controlled duration of effect is needed to ensure similar drug efficacy. Regulatory agencies have recommended the use of partial AUC (pAUC) as an additional exposure measure for relative BA or BE assessments. The pAUC metric describes pharmacokinetic profiles with the focus on quantification of exposures over specific time intervals to support the determination of relative BA or BE for these drug products in relation to respective reference products. The principles and rationales for using pAUCs are included in the US Food and Drug Administration (FDA)'s general BA or BE guidances. Specific pAUC recommendations are also reflected in product-specific guidances for generic drug development published by the FDA. Rationales for the use of pAUCs in relative BA or BE assessments are based on drug-specific and product-specific considerations. This white paper introduces the general framework, including rationales for pAUC recommendations, and provides an overview of the current status, challenges, and the FDA considerations on the use of pAUC for relative BA or BE assessments in the United States.