Sex-by-formulation interaction in bioequivalence trials with transdermal patches.

PURPOSE: The existence of a sex-by-formulation interaction in bioequivalence studies implies that the bioequivalence results (i.e., the test/reference ratio of the pharmacokinetic parameters) obtained in one sex are not similar to those obtained in the other sex. Therefore, results obtained in studies including only males may not be representative of the results obtained in females and vice versa. The best evidence of the existence of a sex-by-formulation interaction has been obtained from a study conducted with transdermal patches. This observation might be caused by the different characteristics of the skin of males and females. The purpose of this work is to investigate the existence of a sex-by-formulation interaction in all bioequivalence studies of transdermal patches submitted to the Spanish Agency for Medicines between 2010 and 2016. METHODS: Only five different products (Buprenorphine-1, Fentantyl-1, Fentanyl-2, Rivastigmine-1 and Rivastigmine-2) that were submitted for registration included nine bioequivalence studies conducted in males and females. As single dose and multiple dose studies are required for registration of transdermal patches in the European Union, more than one study may be available to confirm the existence of a sex-by-formulation interaction. RESULTS: A sex-by-formulation interaction is suggested in six out of 27 datasets (22%), corresponding to two products, and it is statistically significant in three of them (11%). CONCLUSIONS: The sex-by-formulation interaction detected in some pharmacokinetic parameters of some studies is excluded when the study is repeated, which shows that these results are not reproducible. There is no evidence to require bioequivalence demonstration for transdermal patches in males and females separately.

Evaluation of sex-by-formulation interaction in bioequivalence studies of efavirenz tablets.

AIMS: The existence of a sex-by-formulation interaction in bioequivalence studies implies that the bioequivalence results (i.e., the test/reference ratio of the pharmacokinetic parameters) obtained in one sex are not similar to those obtained in the other sex. Therefore, results obtained in studies including only males would not be representative of the results that would have been obtained in females and vice versa. Recently, a sex-by-formulation interaction has been reported in a study for efavirenz tablets. The purpose of this paper is to investigate whether a sex-by-formulation interaction is actually observed in the bioequivalence studies conducted with efavirenz tablets. METHODS: The existence of sex-by-formulation interaction was investigated in the two studies conducted in our centre, where the same test and reference products were investigated in a pilot study with 12 subjects and a pivotal study with 36 subjects. RESULTS: In the pilot study, the point estimates for the test/reference ratio of geometrics means of Cmax in females and males were more than 20% different (95.42% vs.79.38%, i.e., 120.21%), but in a subsequent pivotal study the difference was less than 2% (111.14% vs. 109.98%, i.e., 101.66%). CONCLUSIONS: A sex-by-formulation interaction is suggested in the study with a small sample size, but it disappears when the study is repeated with a larger sample size. In conclusion, the analysis of subgroups should be conducted with caution when the size of the subgroups is not powered to show bioequivalence. There seems to be no reason to require bioequivalence studies for efavirenz in both sexes.

Sex Effect on Average Bioequivalence.

PURPOSE: Generic formulations are by far the most prescribed drugs. This scenario is highly beneficial for society because medication expenses are significantly reduced after expiration of the exclusivity period conceded to the branded name drug. Correspondingly, these formulations must be adequately evaluated to avoid drug inefficacy and toxicity in the overall patient population. Bioequivalence studies are the only in vivo evaluation that a generic drug must overcome to reach the market. These clinical trials have not been exempt from underrepresentation of female subjects and a lack of sex-based analysis. Frequently, conclusions obtained in men are extrapolated to women. Furthermore, the obtained results are not analyzed to determine sex differences. The aim of this study was to discuss the effect that male and female differences in gastrointestinal physiology can have on bioequivalence conclusions and to show why a sex-based analysis must be conducted in these studies to improve the evaluation of generic drugs. METHODS: This discussion was based on observed sex differences in product bioavailability discrimination (sex-by-formulation interaction) and on residual variability through an analysis of average bioequivalence data previously reported by other researchers and data collected by our center. Bioequivalence studies of oral formulations, with a 2-period, 2-sequence, 2-treatment random crossover design performed in healthy subjects with at least 6 subjects of each sex, were included. In addition, the bioequivalence conclusion that would have been reached in each study if performed with only 1 sex was estimated. FINDINGS: The data reveal that differences in both product bioavailability discrimination and residual variability occur with a significant incidence in bioequivalence studies. In either Cmax or AUC, a significant sex-by-formulation interaction was present in 1 of 3 reviewed studies, whereas differences in residual variability between sexes were significant for >50% of studies. Moreover, the performed estimations suggest that the reported bioequivalence conclusions were not verified in at least 1 sex for 1 of 3 studies and were not verified in men and in women for 1 of 6 studies. IMPLICATIONS: This research shows that extrapolation of bioequivalence results from the male population to the female population is not always valid. Bioequivalence studies must therefore be performed with both male and female subjects in similar proportions. Sex-based analysis in bioequivalence can improve study design, enhance the representativeness of conclusions, and provide important information regarding formulation performance, thereby promoting the efficacy and safety of generic drugs.

Sex-by-formulation interaction assessed through a bioequivalence study of efavirenz tablets.

Although sex-related differences in gastrointestinal physiology have been vastly reported, its impact on drug oral bioavailability and bioequivalence (product discrimination) is often ignored. On this work results from an average bioequivalence study between tablets containing 600mg of the antiretroviral efavirenz (EFV), carried out with 14 healthy subjects (8 female and 6 men) in a randomized 2-period, 2-treatment crossover design, are analyzed from a sex-based approach. Sequences were balanced within each sex group. Considering all subjects, no differences were observed on EFV absorbed amount, as shown by the estimated 90CI of the AUC96 Test/Reference bioequivalence ratio (T/R): 0.950-1.05. However, results were not conclusive due to the 90CI for CMAX T/R was 0.743-1.07. Over this parameter, a significant sex-by-formulation interaction was detected: 90CI CMAX T/R was 0.838-1.36 in women and 0.540-0.920 in men; with a 52% relative difference between point estimates. Formulation differences were therefore evidenced only by male subjects. In vitro dissolution and disintegration tests for both products were carried out in two aqueous media: A) SLS 0.25% and B) HCl/KCl pH1.2. T/R results for dissolution efficiency and tablet disintegration times of formulations in both A and B media were highly correlated with CMAX T/R bioequivalence results observed in women and men respectively, showing that a dissimilar gastrointestinal environment between sexes affected EFV oral absorption. This work shows how sex-by-formulation interaction can affect bioequivalence conclusions. Sex effect on product discrimination should be specially disclosed in bioequivalence studies, mainly for drugs aimed to be given to both sexes.