Rationale and conditions for the requirement of chiral bioanalytical methods in bioequivalence studies

Abstract

Purpose: The aim of the present work was to assess the need for chiral bioanalytical methods in bioequivalence studies.

Methods: The samples from a bioequivalence study of two ibuprofen 2% oral suspensions that had shown bioequivalence for AUC and C(max), but not for t(max) (medians of 2.0 and 0.75 h) with a non-chiral method were assayed with a chiral method to investigate whether there was an actual difference in the rate of absorption within the limits of C(max) and AUC bioequivalence.

Results: The non-chiral method and the sum of concentrations of both enantiomers obtained with the chiral method gave a similar outcome (90% CI C(max) non-chiral: 82.77-96.09, sum of enantiomers: 82.19-98.23; 90% CI AUC(t) non-chiral: 107.23-115.49, sum of enantiomers: 105.73-121.35). However, the chiral method showed differences in AUC and C(max) that resulted in non-bioequivalence for the individual enantiomers (90% CI C(max) S-ibuprofen: 76.05-91.36, R-ibuprofen: 87.84-113.05; 90% CI AUC(t) S-ibuprofen: 96.67-105.86, R-ibuprofen: 118.86-142.24). The differences in the pharmacokinetics of each enantiomer, and thus in the enantiomer concentration ratio, were dependent on the rate of absorption.

Conclusions: Due to the fact that in bioequivalence studies the rate of absorption of the new product is unknown, chiral bioanalytical methods should be employed for chiral drugs, such as ibuprofen, whose enantiomers exhibit different pharmacodynamic characteristics and whose enantiomer concentration ratio might be modified by the rate of absorption, irrespective of whether the eutomer is the minor enantiomer or the similarity of the pharmacokinetics of the enantiomers at a given rate of absorption.