Metabolites and bioequivalence: past and present.

Although it is widely recognised that measurement of metabolite concentrations is crucial to understanding the clinical pharmacology characteristics of a new molecular entity, a clear consensus on the role of metabolites in the assessment of bioequivalence has never been achieved within the scientific community. However, a regulatory policy for the role of metabolites in bioavailability and bioequivalence has been established by the US FDA. One school of thought believes that the parent drug alone is sensitive to picking up formulation differences, whereas another school of thought believes that establishing bioequivalence criteria on all the species that contribute to safety and efficacy is the only way to ensure the switchability of two products. In this paper, a brief review of the pharmacokinetics of metabolites under different scenarios is presented and the history of the role of metabolites in the assessment of bioequivalence is summarised. Relevant examples from the literature illustrating conflicting opinions on the need for the measurement of metabolites in bioequivalence studies are given. Cases from the literature in which the parent drug is able to meet the 90% confidence intervals while the metabolite(s) fail to do so, and vice versa, are presented to illustrate the difficulty in choosing the pertinent entity to measure. The relevant current US FDA policy and guidelines related to bioavailability and bioequivalence are discussed and contrasted with the rules and regulations applicable in Canada and Europe.