What should be measured in a bioequivalence study: parent drug, metabolite or enantiomers?

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SFDA: “In principle, evaluation of bioequivalence should be based upon measured concentrations of the parent compound. The reason for this is that Cmax of a parent compound is usually more sensitive to detect differences between formulations in absorption rate than Cmax of a metabolite.” (SFDA BE v3.1 · 3.1.5 Characteristics to be investigated – Parent compound or metabolites) “Hence, the use of a metabolite as a surrogate for active parent compound is expected to be accepted only in exceptional cases.” (SFDA BE v3.1 · 3.1.5 Characteristics to be investigated – Use of metabolite data as surrogate for active parent compound) “The use of achiral bioanalytical methods is generally acceptable. However, the individual enantiomers should be measured when all the following conditions are met: 1) the enantiomers exhibit different pharmacokinetics 2) the enantiomers exhibit pronounced difference in pharmacodynamics 3) the exposure (AUC) ratio of enantiomers is modified by a difference in the rate of absorption.” (SFDA BE v3.1 · 3.1.5 Characteristics to be investigated – Enantiomers) EU: “Demonstration of BE should be based on the analysis of the parent drug …” (ICH M13A · 2.1.7.1) “However, some prodrugs are rapidly eliminated resulting in difficulties in demonstrating BE based on parent drug data, as the parent drug levels are too low to allow reliable bioanalytical measurement. In this situation, it is acceptable to demonstrate BE based on a primary metabolite, i.e., a first-step metabolite of the parent drug, without measurement of the parent compound.” (ICH M13A · 2.1.7.1) “The use of an achiral bioanalytical assay to measure the racemate is generally acceptable. However, a stereoselective assay measuring individual enantiomers in BE studies should be employed when it is known that all of the following conditions have been met: a) the enantiomers exhibit different pharmacodynamic properties, b) the enantiomers exhibit different PK properties, and c) the exposure (AUC) ratio of enantiomers is modified by a difference in the rate of absorption.” (ICH M13A · 2.1.7.2) US FDA: “FDA generally recommends that applicants measure only the parent drug, rather than metabolites, because the concentration-time profile of the parent drug is usually considered more sensitive to changes in formulation performance than a metabolite, which is more reflective of metabolite formation, distribution, and elimination.” (FDA ANDA BE 2026 · V.A.1) “Primary active metabolite(s) should be measured if they (1) are formed substantially through presystemic metabolism (i.e., gut wall or gut lumen metabolism) and (2) contribute significantly to the safety and/or efficacy of the product.” (FDA ANDA BE 2026 · V.A.1) “For BE studies, FDA recommends using an achiral bioanalytical assay to measure the racemate.  FDA recommends measuring individual enantiomers in BE studies only when all the following conditions have been met:  (1) the enantiomers exhibit different PD characteristics, (2) the enantiomers exhibit different PK characteristics, and (3) the exposure (AUC) ratio of enantiomers is modified by a difference in the rate of absorption.” (FDA ANDA BE 2026 · V.A.2) WHO: “The concentration–time profile of the API is more sensitive to changes in formulation performance than a metabolite, which is more reflective of metabolite formation, distribution and elimination.” (WHO TRS 1052 Annex 8 · 7.4.9) “In rare cases it may be necessary to measure concentrations of a primary active metabolite rather than those of the API if concentrations of the API are too low to allow reliable analytical measurement in blood, plasma or serum for an adequate length of time, or when the parent compound is unstable in the biological matrix.” (WHO TRS 1052 Annex 8 · 7.4.9) “A non-stereoselective assay is acceptable for most bioequivalence studies. A stereospecific assay measuring the individual enantiomers should be employed when the enantiomers exhibit different pharmacokinetic properties

What should be measured in a bioequivalence study: parent drug, metabolite or enantiomers?

SFDA Saudi Food and Drug Authority

EU European Union

US FDA US Food and Drug Administration

WHO World Health Organization

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