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 (Cmax) 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 were 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 Cmax), 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 Cmax) is approximately 13% and approximately 35%, counting by data sets and studies, respectively. Mean sex-related differences of > or = 20% in the pharmacokinetic parameters for the reference product were observed in 39% of the data sets (AUC or Cmax). In approximately 28% of the data sets, these differences were statistically significant. The frequency was approximately 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.