Effect of the stereospecific vs non-stereospecific analytical method on the drug bioequivalence: case study of bicalutamide tablets
Author(s): Varad R. Pradhan, M. V. Rathnam*, Siddheshwar Patankar, S. B. Dharap, Ashutosh Pudage
Abstract
Stereoselectivity is an important consideration in the risk assessment of pharmaceuticals. Chiral separation, enantioselective analysis and asymmetric synthesis technology is rapidly improving, principally driven by the pharmaceutical industry. Therefore it may be reasonable to expect manufacturers to carry out toxicological testing using the individual pure enantiomers of chiral compounds and to justify whenever chiral products are manufactured as the racemates. There are numerous examples in the scientific literature of individual enantiomers displaying different biological effects. Differential metabolism of chiral compounds has been demonstrated for a wide variety of pharmaceuticals; however, differential effects can also result from other factors. The most obvious difference between enantiomers is intrinsic toxicological effect (pharmacodynamics), where one enantiomer has a different mode of action from another or may even be non-toxic. A better understanding of when stereoselective pharmacokinetic and bio-availability investigations are needed or not needed can be obtained by exploring the relationships that exist between the separate pharmacokinetic parameters of enantiomers and racemates. The present work throws light on one of the most important aspect in bio-availability studies, i.e. the effect of the analytical method (stereospecific vs. non- stereospecific) on the statistical power of the bio-availability and bio-equivalence trials. Bicalutamide (BCT) is a non-steroidal antiandrogen used for the treatment of prostate cancer. BCT as such is a racemic mixture, but most of its pharmacological activity is attributed to its R enantiomer. 50mg dose of BCT was monitored using stereospecific as well as non-stereospecific liquid chromatography tandem mass spectrometric analytical methods. The data revealed that the absolute bio-availability of Bicalutamide tablets is primarily due to R enantiomer. S enatiomer contribution to the bio-availability is negligible, due to its rapid clearance. Interestingly, data revealed that pharmacokinetic parameters for Bicalutamide enantiomers do not follow dose proportion kinetics. Based on the above facts, it may be courageous enough, to state that single enantiomer drug based on R enantiomer for Bicalutamide is promising
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