Bioequivalence and Bioavailability Forum

Hi ele2008,

❝ I just read this article titled "Gender Differences in Drug Bioequivalence: Time to Rethink Practices"¹

I have some mixed feelings about this “Review” – with nine [sic] references; three of them being guidelines. I’m just writing a review about Two-Stage-Designs and digested fifty papers so far – and there is no light at the end of the tunnel yet.

“To achieve BE, the AUC and peak concentrations of the generic drug need to be within 80–120% of the reference drug” referring to FDA’s guidance. 120%?
Followed by “[…] typically BE studies are con­ducted in healthy, young adult male volunteers” referring to EMA’s BE-GL, where I read “Subjects could belong to either sex; however, the risk to women of childbearing potential should be considered”.
ClinTrials, Completed BE Studies in adults: all: 1344, females: 1028, males: 1294.
“Ashiru and colleagues have demonstrated that polyethylene glycol enhances the bioavailability of ranitidine in a dose-dependent manner by up to 63% among men, whereas it decreases absorption among women by up to 24%!”
It’s funny to read a sentence ending with an exclamation mark in a scientific paper. Haven’t seen that before. I guess the authors are on a mission. They performed some cherry-picking in their tables 1&2 from Chen’s retrospective analysis. It is worthwhile to read their paper.* Five of the 26 studies had a sample size of twelve; the median sample size was ten / sex. The background of the analysis was individual bioequivalence (IBE), which was fashionable those days. Have a look at their table III, giving the 95% CI of the female/male standard deviation ratio. I’m not worried at all.
From the conclusions: “[…] we found that in most instances, intra­subject variability in pharma­co­kinetic measures is similar between men and women, although it may indeed be higher for women in a few cases.”
BTW, one of the main reasons why IBE never was implemented was the need for fully replicated designs with high sample sizes. Whereas μ is the first cumulant of the distribution, σ² is its second. With any given sample size a comparison of variances is less powerful than a comparison of means. FDA recently recommended a comparison of variances of NTIDs. The limit of σ_T/σ_R is 2.5…

❝ In the end of article,the author says "Before the twentieth century, men used to perform women’s roles in theater, as a reflection of sexual puritanism. Until recently, women were not allowed to vote in many countries, and this reality continues today in some jurisdictions. It was assumed that men knew what was “good for women.” In the case of regulatory reality, the current approach is clearly not good for women, as the science shows."

Followed by “Women may become pregnant, which is not an issue for short BE studies.” What‽

❝ Really, is women not being included into BE studies a sign of sex discrimination?

I don’t think so. My bioanalytical team (♀:♂ ~ 1:1) was always happy about females in BE-studies because due to their lower body weight / smaller volume(s) of distribution concentrations where higher – less trouble with the LLOQ. Females/males in BE was our standard for two decades. As a wel­comed side-effect the atmosphere in the recreation room of the CRO was much calmer in mixed-sex studies.

See also this thread and this post.

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• Chen M-L, Lee S-C, Ng M-J, Schuirmann DJ, Lesko LJ, Williams RL. Pharmacokinetic analysis of bioequivalence trials: Implications for sex-related issues in clinical pharmacology and biopharmaceutics. Clin Pharmacol Ther. 2000;68(5):510–21. doi 10.1067/mcp.2000.111184