Symmetrical Crossover Designs for Bilateral Pharmacokinetic Drug Interactions
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0092-861 5/2000 Copyright 0 2000 Drug Information Association Inc.
SYMMETRICAL CROSSOVER DESIGNS FOR BILATERAL PHARMACOKINETIC DRUG INTERACTIONS FRANCOIS VANDENHENDE Statistician, Statistical and Mathematical Sciences, Eli Lilly & Company, Mont-Saint-Guibert, Belgium
BENITOJ. CERIMELE Senior Research Scientist, Statistical and Mathematical Sciences, Eli Lilly & Company, Indianapolis, Indiana
Bilateral pharmacokinetic interaction studies are peflormed to test if the coadministration of the two drugs alters the kinetics of either one. For this purpose, standard designs are crossovers in which the two drugs are successively given alone and togethe,: Because the systemic concentration of one drug, A, will be zero when the other drug, B, is given alone and vice versa, two separate analyses for Drugs A and B are required. Two symmetrical designs which generate identical analyses for Drugs A and B are reviewed: the dual balanced two-period and the balanced Latin Square three-period designs. Their efficiency in accurately and precisely estimating direct treatment differences (AB-B) or (AB-A)is compared, when analyzed with a standard linear mixed model that either does or does not include a first-order carry-over effect. From this evaluation, the balanced three-period design is preferred because of its 25% superior efficiency when no carryover effect is present. In the presence of carry-ovel; the three-period design also produces unbiased estimators for the direct treatment and carry-over effects whose variances are proportional to the within-subject variability. Key Words: Bilateral interactions; Pharmacokinetics; Crossover; Carry-over; Efficiency
INTRODUCTION OVER THE PAST FEW months, drug interactions have been the topic of several approved or drafted guidelines (1,2,3), among which great emphasis has been placed on the in vivo assessment of metabolic drug-drug interactions (1,2). The purpose of a metabolic drug interaction trial is to test if one drug (A), the interacting drug, either induces
Taken from a presentation at the DIA “10’ Annual Workshop on Statistical Methodology in Clinical R&D,” April 19-21, 1999. Prague, Czech Republic. Reprint address: Francois Vandenhende, Statistical and Mathematical Sciences, Eli Lilly & Company, 11 rue Granbonpre, B-1348 Mont-Saint-Guibert, Belgium.
or inhibits the metabolism of another drug (B), the substrate. A potential modification of the metabolism of B could induce an alteration of its pharmacokinetic profile and/or its pharmacodynamic activity (4) that could necessitate dosage adjustment of the substrate (B), when given together with the interacting drug (A). The recommended approach for studying such pharmacokinetic interactions is to give, in a crossover setting, the substrate (B) alone and together with the interacting drug (A). The need for a dose adjustment is then assessed based on the 90% confidence interval on the difference or ratio of mean pharmacokinetic parameters between the two treatment groups (AB-B) (1,2,5,6).
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