ABSTRACT
Bioequivalence (BE) studies usually consist of a comparison of blood, plasma, or serum drug concentration-time profiles of a test and a reference formulation with regard to the extent and rate of the entry of the active ingredient into the blood circulation. Under certain circumstances, urinary excretion data may also be used (1). Generally, two formulations of the same drug are considered bioequivalent if their measures of extent [area under the plasma concentration-time curve (AUC)] and rate [peak plasma concentration (Cmax)] of drug entry into the systemic circulation do not differ significantly. The literature over the past several years is replete with theories and guidelines regarding experimental design, type of assay, and data analysis for BE studies of nonracemic pharmaceuticals (2-7). For racemic drugs, often the enantiomers possess different pharmacodynamic or pharmacokinetic characteristics (8-10). Since the 1990s, guidelines have been developed dealing with the BE of racemic drugs as well (11-14), although the issue has still not been quite settled. There are arguments, both in favor and against the need for chiral assays in these studies (15-22). Despite the availability of robust and facile analytical methods for separation and analysis of individual enantiomers, the approach is considered to be laborious and costly compared with the nonstereospecific
analytical procedures. Therefore, justification for requiring chiral assays for BE studies of chiral drugs may best be treated on a case-by-case basis. It is important to note, however, that sometimes applications for the approval of new racemic drugs may be based on the pharmacokinetic, pharmacodynamic, and/or toxicokinetic data for the individual isomers. This, very likely, calls for stereochemical data for approval of generic products regardless of the agencies’ guidelines. The currently available guidelines and their limitations with regard to the BE of racemic drugs will be addressed in this chapter.
