Beyond the Male Default- Why Sex Matters in Drug Metabolism, ADME and Clinical Trials

Have you ever wondered whether the standard drug dose we all follow is actually the standard? The first historically recorded clinical trial was performed by a Scottish naval physician, James Lind, in 1747 to discover a cure for scurvy(ascorbic acid deficiency), and it featured 12 of his male co-sailors.

Ever since, for much of the history of biomedical research, males have been considered the default for testing the effects of drugs on the human body.

For the safety of women and their offspring, women of fertile age were excluded from clinical trials, turning male physiology into the reference of the species in medical research and drug discovery.

In 1993, the National Institutes of Health (NIH) Revitalisation Act in the United States mandated the inclusion of women in NIH-funded clinical trials, but many investigators did not follow this policy or failed to analyse the results by sex, minimising the effectiveness of this mandate. Although females were included in clinical trials before, the representation and analysis remained inadequate until the 1991 Women’s Health Initiative proved to be a great milestone for female representation in research trials.

The historical exclusion of female data from pharmacological studies has led to uniform dosing guidelines that treat the male body as default, despite clear chemical differences in drug processing. Various physiological and hormonal differences between males and females significantly alter the drug's ADME, and recent findings suggest the need for sex-inclusive clinical trials to assess efficacy and safety.

The liver isozyme that is responsible for the metabolism of the majority of drugs is cytochrome P450; recent studies show that there is a significant difference in its action depending on the sex of the patient. These differences are partly influenced by sex hormones such as estrogen, progesterone and testosterone.

Hence, PK of drugs may vary in premenopausal, postmenopausal and pregnant women, which explains how dose may vary based on the given life stage.

A 2020 study with 86 FDA-approved drugsshowed that 76/86 of the drugs that were tested showed that women had higherpharmacokinetics values than men; 59/86 drugs showed clinically identifiable adverse drug reactions, and almost 96% of the drugs associated a higher incidence of adverse drug reaction in women along with PK differences.

A valid and important study that supports the above findings is the example of Zolpidem, a prescription sedative-hypnotic used short-term for the treatment of severe insomnia.  

A clinical study including 15 male and 15 female healthy subjects was given a single oral dose of zolpidem (10 mg), and blood samples 12 hours post-administration werecollected to evaluate the drug pharmacokinetics and pharmacodynamics. CYP3A4 activity was measured using 4β-hydroxycholesterol, an endogenous metabolite.

After evaluation, findings showed that the mean maximum plasma concentration and area under the plasma concentration–time curve were higher for females than for males (9.9% and 32.5%, respectively). Zolpidem was absorbed rapidly, reaching maximum concentrations within 1 h in most subjects. The median time to reach Cmax (Tmax) was 0.9 and 1.1 h for males and females, respectively. Mean plasma levels were higher in female subjects than in male subjects at all time points.

This shows that females show a lower apparent clearance rate for Zolpidem as compared to males.

Mean plasma concentration–time profiles of zolpidem

Such significant differences may lead to the risk of next-morning impairment.

In 2013, the FDA reported that femalesclear zolpidem more slowly than males and specifically states that women are more susceptible to next-morning impairment and that high residual concentrations can impair activities requiring alertness, including driving; thus, the recommended dose for women was changed from 10mg to 5 mg.

Such studies suggest that testing for females in the drug approval process is essential, but simply including women in a clinical trial does not guarantee that sex-related differences in drug response will be identified. For meaningful female representation, women must be adequately enrolled, and their data should be analysed separately for pharmacokinetic, pharmacodynamic, efficacy and safety outcomes. This is particularly important for ADME, as differences in body composition, hormonal status, drug-metabolisingenzymes, transporters and renal function can influence drug exposure. If male and female data are combined into a single average, clinically relevant differences in parameters such as Cmax, AUC, clearance and half-life may be concealed. Furthermore, female participants are not a biologically uniform group; factors such as age, menopausal status and hormonal therapy may also influence drug disposition. Therefore, modern clinical trials should move beyond simply asking whether women were included and instead ask whether the study was sufficiently designed and powered to identify meaningful sex-related differences in drug response. The objective is not to assume that women require different treatment, but to generate enough evidence to determine when such differences are clinically important.

So, when a new drug is discovered, we should realise that clinical trials should not ask whether women can fit into the existing standard; they should ask whether the standard itself was built to represent them. Because when the same dose can produce a different exposure, “one dose fits all” may not always mean “one dose is safe for all.”

-By Ananya Vani ( T.Y BPHARM)

References-

(Administration, 2013)

(Mauvais-Jarvis F, n.d.)

(Yoon, n.d.)

(Zucker I, 32503637, & PMC7275616., n.d.)