Racemates, bioavailability/bioequivalence studies

Stereoisomer Assays. There are many drugs that are administered as racemic mixtures. They may undergo stereoselective metabolism and/or elimination, and one isomer may be more active than the other. Therefore, there is the need to develop and validate bioanalytical assays for stereoselective determination in bioavailability/bioequivalence studies. All methods used for measurement of stereoisomer should be validated (with emphasis on stereospecificity). For bioequivalence studies of an existing racemic product, a stereospecific assay is not required if the rate and extent of profiles are superimposable (within the usual statistical boundaries) [3,23]. 

For bioavailability studies, the parent compound or the active moiety and the active metabolites should be measured if analytically feasible. For bioequivalence studies, the measurement of the parent compound is desirable, unless the parent drug levels in the plasma or serum are too low to allow reliable measurements. In addition to measuring the parent, the measurement of the metabolite is important when it contributes to either safety or efficacy of the drug product. The bioequivalence criterion is applied to the parent with supportive evidence from the metabolite measurements. Similarly, measurement of enantiomers or racemate may be necessary as appropriate. 

For bioavailability studies, measurement of individual enantiomers may be important. For bioequivalence studies, this guidance recommends measuring of the racemate using an achiral assay. Measurement of the individual enantiomers in bioequivalence studies is recommended only when all of the following conditions are met (Fig. 1) (1) the enantiomers exhibit different pharmacodynamic characteristics (2) the enantiomers exhibit different pharmacokinetic characteristics (3) primary efficacy/safety activity resides with the minor enantiomer and (4) nonlinear availability is present (as expressed by a change in the enantiomer concentration ratio with a change in the input rate of the drug) for at least one of the enantiomers. 

Midha, K. Gordon McKay. Rawson, M. Hubbard, J. The impact of stereoisomerism in bioequivalence studies. J. Pharm. Sci. 1998, 87, 797 802. Karim, A. Enantioselective assays in comparative bioavailability studies of racemic drug formulations nice to know or need to know J. Clin. Pharmacol. 

Our first stereospedfic bioequivalence evaluation using verapamil formulations was a pilot study conducted in 24 healthy male volunteers. The study compared the bioavailability of two sustained-release dosage forms and an immediate release formulation of racemic verapamil in a three-way cross-over study. Table 2 summarizes the results observed for verapamil. Table 3 the results for norverapamil. First, pharmacokinetic... 

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