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 involving both sexes. A total of 94 data sets [47 each for the areas under the plasma concentration-time curve (AUC) and maximum concentration (C-max)] were used. ANOVA was performed. Three statistical models were used to estimate population means and intrasubject variability between sexes, as well as sex-by-formulation interactions. Comparisons mere made by use of confidence intervals, magnitude of observed differences, and statistical significance (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 significantly higher variability. Although fewer, there were examples with higher variability in men. With a 20 percentage point difference used in the test-over-reference mean ratios between sexes as a signal of sex-by-formulation 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 pharmacokinetic 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 differences were statistically significant. The frequency was similar to 15% after body weight correction. Conclusions: In general, men and women have similar intrasubject variability. Where variability differs between sexes, there is a suggestion that higher variability in women may be more frequent. The data also suggest that a sex-based subject-by-formulation interaction can occur, although the frequency 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 Administration gender guideline that women not be excluded from bioequivalence trials. (Clin Pharmacol Ther 2000;68:510-21.).