Why does it matter when clinical drug trials don’t include women?
Let's break down the difference between female and male pharmokinetics.
Key Takeaways
Pharmokenitics is the study of drug transit time in the body.
The majority of the drugs we use today haven’t seen pharmokenitic studies on women.
The FDA is back-tracking recommended doses as researchers catch up on female drug reactivity.
The laws have changed but that doesn’t repair the decades of missing data from women being excluded from trials. You can help researcheres catch up.
Pharmokinetics is a fancy term used to describe how a drug moves through the body, starting from how it is taken in, how it moves throughout, and how it is removed or expelled. Studying pharmokinetics gives the medical community an understanding of how the body responds to whatever drug is being tested.
The key components of drug pharmokinetics are called ADME (absorption, distribution, metabolism, and excretion). Let’s take a look at Ambien, for example. Ambien is a sleep medication taken orally. It is absorbed in the small intestine and then circulates the body via the bloodstream until it is broken down in the liver and removed from the body by the kidneys in urine. That gives us the full ADME for Ambien.
ADME is affected by various factors such as body fat composition, hormones, liver enzymes [1]. When developing a drug, researchers measure the time it takes for each ADME component to ensure the drug’s safety. All of these factors differ between men and women so what happens when a clinical trial doesn’t include any or enough women?
Are today’s drugs safe for women?
The obvious answer is that we can’t conclude that the drug is safe for women.
Unfortunately, for a large swath of history, women have been excluded from studies or (still to this day) sex-specific results aren’t reported. Thus, even with recent progress with including women in clinical trials, there are still many drugs that were not trialed on women (proportionally or at all), yet are currently approved by the Food and Drug Administration (FDA). This means that women are still being prescribed drug dosages meant for the average white male’s weight and metabolism [2].
Let’s return to Ambein (zolpidem), a widely prescribed insomnia medication in the U.S.. Twenty-one years after its FDA approval in 1992, the FDA announced that it was halving Ambien’s dosage for women. This shift was triggered after the company Intermezzo sought FDA approval for an Ambien-based nasal spray in 2008. The FDA repeatedly rejected the drug’s approval due to concern that the drug caused cognitive impairment in women the morning after usage posing a threat to female drivers.
Initially, the Intermezzo fought back, denying the claim that there were any sex based differences in the drug’s effect. They even claimed that female drivers being sleep deprived was a greater public health concern! The manufacturer maintained the stance that there was no ‘statistical difference’ between male and female dosing and the drug response that could be explained by weight [3].
Following a lengthy battle with the FDA, Intermezzo later themselves reported:
“The 1.75 mg dose in females appears to have a similar effect as the 3.5 mg dose in males… This lends further support that the 1.75 mg dose can be effective in females, since for a given dose, the plasma zolpidem concentrations are often higher than in males… adjusting by body weight doesn’t alleviate the concern that many females do have higher plasma concentration levels at the four-hour post-dosing time point.” [4]
What was most alarming is that Intermezzo didn’t perform any new research and simply analysed data they already had available [4]!
Separate studies have established that women have lower clearance of zolpidem than men, meaning the drug stays in the female body longer at the same dose. This results in higher drug levels in women’s blood (40–50% higher) compared to men after taking the same dose [5].
Just another example to keep you up at night is Valium (diazepam), a common anxiety and insomnia medication which first entered the US market in 1963 [6][7]. Valium was widely marketed as “mothers little helper ” despite never having been tested on women [7]. In 2016, a study on rats by Silva et al, found that the varying progesterone levels of the female menstrual cycle impacted the effectiveness and side effects of the drug [8].
How can you change things?
The biomedical research community is acutely aware that sex based differences can be seen not just in humans but in animals and cell cultures [9]. Since 2014, the primary research and funding body for biomedical research in the U.S., the National Institutes of Health, mandated that all of its funded preclincal and clinical research results must account for sex as a biological variable [10]. However, more effort needs to be made regarding standardising the analysis and reporting of sex-based differences across other research, and funding bodies are needed to make strides in tackling the evident research gap faced by 51% of our population [11].
But that won’t fix the data that was missed during the past several hundred years of Western medicine. That’s where Asterisk comes in. We’re building a daily health check-in app that shares you anonymized status updates with researchers. In turn, you receive personalized health trends to help you better advocate for yourself with doctors AND vote on the disorders we work to improve. Help us make women’s health care better!
Bibliography
1.Chu T. Gender Differences in Pharmacokinetics [Internet]. Uspharmacist.com. 2014. Available from: https://www.uspharmacist.com/article/gender-differences-in-pharmacokinetics
2.Schiebinger L. Women’s health and clinical trials. Journal of Clinical Investigation. 2003 Oct 1;112(7):973–7.
3.Zhao H, DiMarco M, Ichikawa K, Boulicault M, Perret M, Jillson K, et al. Making a “sex-difference fact”: Ambien dosing at the interface of policy, regulation, women’s health, and biology. Social Studies of Science. 2023 May 6;030631272311683-030631272311683.
4.CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 022328Orig1s000 MEDICAL REVIEW(S) [Internet]. [cited 2024 Dec 11]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022328Orig1s000MedR.pdf
5.Greenblatt DJ, Harmatz JS, Singh NN, Steinberg F, Roth T, Moline ML, et al. Gender differences in pharmacokinetics and pharmacodynamics of zolpidem following sublingual administration. The Journal of Clinical Pharmacology. 2013 Nov 27;54(3):282–90.
6.Cleveland Clinic. Diazepam (Valium): Uses & Side Effects [Internet]. Cleveland Clinic. 2024. Available from: https://my.clevelandclinic.org/health/drugs/20942-diazepam-tablets
7.Calcaterra NE, Barrow JC. Classics in Chemical Neuroscience: Diazepam (Valium). ACS Chemical Neuroscience [Internet]. 2014 Feb 27;5(4):253–60. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990949/#:~:text=Diazepam is the generic name,billion tablets sold in 1978.
8.Silva AF, Sousa DS, Medeiros AM, Macêdo PT, Leão AH, Ribeiro AM, et al. Sex and estrous cycle influence diazepam effects on anxiety and memory: Possible role of progesterone. Progress in Neuro-Psychopharmacology and Biological Psychiatry [Internet]. 2016 Oct 3 [cited 2022 Mar 22];70:68–76. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0278584616300756
9.Clayton JA, Collins FS. Policy: NIH to balance sex in cell and animal studies. Nature News [Internet]. 2014 May 15;509(7500):282. Available from: https://www.nature.com/news/policy-nih-to-balance-sex-in-cell-and-animal-studies-1.15195
10.NIH Policy on Sex as a Biological Variable | Office of Research on Women’s Health [Internet]. orwh.od.nih.gov. Available from: https://orwh.od.nih.gov/sex-gender/orwh-mission-area-sex-gender-in-research/nih-policy-on-sex-as-biological-variable
11.Safdar B, Ona Ayala KE, Ali SS, Seifer BJ, Hong M, Greenberg MR, et al. Inclusion of Sex and Gender in Emergency Medicine Research—A 2018 Update. Kline JA, editor. Academic Emergency Medicine. 2019 Feb 5;26(3):293–302.