title: Pharmacokinetic analysis of bioequivalence trials: implications for sex-related issues in clinical pharmacology and biopharmaceutics.
abstract: OBJECTIVE
  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.
authors: Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD 20857, USA. Chenme@cder.fda.gov
authors: M L
authors: ML
authors: Chen
authors: S C
authors: SC
authors: Lee
authors: M J
authors: MJ
authors: Ng
authors: D J
authors: DJ
authors: Schuirmann
authors: L J
authors: LJ
authors: Lesko
authors: R L
authors: RL
authors: Williams
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D016001:Confidence Intervals; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D010599:Pharmacokinetics; D012727:Sex Characteristics; D013810:Therapeutic Equivalency
chemical_list: D003692:Delayed-Action Preparations