Influence of Feeding and Analytical Method on the Bioequivalence of a Racemic Drug Undergoing Enantioselective Enterohepatic Recycling

Abstract Two crossover bioequivalence trials of an enantioselectively enterohepatic recycled drug, carprofen, were conducted in dogs with the same racemic oral formulation to determine: (i) the influence of feeding patterns, and (ii) the effect of the analytical method (enantioselective vs non-enantioselective) on the statistical power of the trials. The first trial was conducted with a standard feeding protocol and the second with a special feeding protocol selected to ensure constant biliary flow into the duodenum. Using a non-enantioselective technique, 90% confidence intervals provided conclusions of bioequivalence in 100% of the cases for both area under the plasma concentration versus time curve (AUC) and maximum plasma drug concentration (Cmax) with the special feeding protocol, but only 50% for AUC and 13% for Cmax with the standard feeding protocol, suggesting that a feeding pattern that diminishes plasma drug concentration rebound for an enterohepatically recycled drug increases the power of a bioequivalence trial. Whatever the feeding protocol, an enantioselective method decreased the power of the trials for AUC but increased the power of the trials for Cmax. For an enterohepatically recycled drug, feeding pattern can influence the power of a bioequivalence trial, and the analytical technique that provides the greatest power depends on the assessed bioequivalence parameter and the feeding pattern. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association