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.

Sedative-hypnotic drugs and the risk of hip fracture.

A retrospective cohort study was conducted in individuals 65 years of age and older using Medicaid-reimbursed claims to assess the risk of hip fracture in users of two sedative-hypnotic drugs, triazolam and temazepam. Using the triazolam cohort as the referent group, the rate ratio was 0.92 (95% confidence interval, 0.72 to 1.17) for hip fracture with temazepam. Stratifying by age, sex, race, residence, time enrolled in Medicaid, prescription number, combinations of these, and several other potential confounding variables did not materially change the results. Compared with the short-acting benzodiazepine hypnotic temazepam, use of triazolam, an ultra-short-acting benzodiazepine hypnotic, did not decrease the risk of hip fracture. This study did not determine that either drug, compared with no use in an insomniac control group, increases the risk of hip fracture. However, because sedative-hypnotic drugs have been found in other studies to increase the risk of falling and hip fracture, they should be used with caution, especially in the elderly.