Pharmacokinetic analysis of bioequivalence trials: Implications for sex-related issues in clinical pharmacology and biopharmaceutics

Objectives: To address the questions of whether women should be included in bioequivalence trials and whether dosage adjustment may be needed in women relative to men. Methods: Sex-related analysis was conducted for 26 bioequivalence studies i nvolving both sexes. A total of 94 data sets [47 each for the areas under t he plasma concentration-time curve (AUC) and maximum concentration (C-max)] were used. ANOVA was performed. Three statistical models were used to esti mate population means and intrasubject variability between sexes, as well a s sex-by-formulation interactions. Comparisons mere made by use of confiden ce intervals, magnitude of observed differences, and statistical significan ce (alpha = .05). Results: With some exceptions, intrasubject variabilities were similar for men and women. In about 10% of the data sets (AUC or C-max), women had sign ificantly higher variability. Although fewer, there were examples with high er variability in men. With a 20 percentage point difference used in the te st-over-reference mean ratios between sexes as a signal of sex-by-formulati on interaction, the frequency of this interaction (AUC or C-max) is similar to 13% and similar to 35%, counting by data sets and studies, respectively . Mean sex-related differences of greater than or equal to 20% in the pharm acokinetic parameters for the reference product were observed in 39% of the data sets (AUC or C-max). In similar to 28% of the data sets, these differ ences were statistically significant. The frequency was similar to 15% afte r body weight correction. Conclusions: In general, men and women have similar intrasubject variabilit y. Where variability differs between sexes, there is a suggestion that high er variability in women may be more frequent. The data also suggest that a sex-based subject-by-formulation interaction can occur, although the freque ncy may be low Sex-related differences in pharmacokinetics are apparent in many drugs studied. Dosage adjustment with body weight may be warranted for drugs that exhibit a steep dose-response curve. Although exploratory, the results of this study support recommendations of the 1993 Food and Drug Adm inistration gender guideline that women not be excluded from bioequivalence trials. (Clin Pharmacol Ther 2000;68:510-21.).