BIOEQUIVALENCE OF CONTROLLED-RELEASE CALCIUM-ANTAGONISTS

In this review, several deficiencies of publisged bioequivalence studi es for controlled-release calcium antagonists have become apparent. As a consequence, some of the published conclusions based on such studie s must be viewed with care. A proper statistical analysis of bioequiva lence is not frequently reported. A proper statistical analysis of the pharmacokinetic variables involves the calculation of 90% confidence intervals (CI) for the test : reference ratio of the means of the phar macokinetic variables of the test and reference product. The CI must f all completely within the predetermined bioequivalence range (usually 0.8 to 1.25) for the products to be declared bioequivalent. Serious me thodological errors, such as a conclusion of bioequivalence based on a lack of statistically significant difference between products, and co nversely, a conclusion of bioequivalence because of a statistically si gnificant difference, or because of a mere failure to show bioequivale nce, are still made. With calcium antagonists in particular, an assess ment of the rate of absorption and of the maximum concentration is imp ortant, as those characteristics may have implications for the safety profile with this class of drugs. As a minimum, in single doses studie s the maximum concentration (C-max), and the time to the maximum conce ntration (t(max)), and in multiple-dose studies the C-max, and the pea k-trough fluctuation (%PTF) must be considered. SOme bioequivalence st udies, of calcium antagonists are deficient in this respect. To show b ioequivalence for controlled-release formulations, multiple-dose studi es are required but some published bioequivalence studies contain only single-dose assessments. Similarly, bioequivalence studies under fed conditions are rarely published, although food may have a significant effect on the absorption rate of these drugs. SOme calcium antagonists , such as verpamil, show stereoselective pharmacokinetics, so that ena ntiomers may have to be investigated, Unfortunately, few of the publis hed studies of controlled-release calcium antagonists satisfy all requ irements. One would expect that data submitted to regulatory authoriti es for approval of generic formulations are more complete: published d ata are in many casts not satisfactory.