By Shin Jie Yong
Established risk factors for ADRs include old age, liver and renal issues, and female sex. Over two-thirds of ADRs cases are females. Female patients also have nearly a two-fold increased risk of ADRs.
Although sex-specific differences in drug metabolism exist, both sexes are still medicated the same. Hardly any adjustments to dosage were practised.
“Most drugs are prescribed to women and men at the same dose,” integrative biology emeritus professor Irving H. Zucker and psychoneuroimmunology professor Brian J. Prendergast wrote in their 2020 paper printed in Biology of Sex Differences, entitled “Sex differences in pharmacokinetics predict adverse drug reactions in women.
In this research, the professors reviewed over 5,000 medical papers on drugs approved by the US Food and Drugs Administration (FDA). They found that 86 drugs are metabolised differently in males and females.
However, 86 is still an underestimate as there are other drugs with sex-specific effects in clinical practice – only that they lack pharmacokinetics (the study of drug metabolism) data. A 2017 research review, for instance, estimated that 30 per cent of drugs lack sex-specific pharmacokinetics data.
Over 90 per cent of these 86 drugs have an ADR bias towards women, examples including anxiolytics, antidepressants, cardiovascular medications and painkillers.
Why? The main reason is that these drugs have a slower clearance rate in females than males with the same dosage. So these drugs remain active for longer in the blood circulation of women.
These sex-specific differences in pharmacokinetics are also not explained by body weight, which is another known factor affecting drug metabolism.
An example is the popular sleeping pill zolpidem, marketed as Ambien, which that persists longer in the system of females than males. Women taking zolpidem often experience drowsiness and profound cognitive deficits the next morning, which might lead to driving accidents. But the FDA has already cut the prescribed dosage of zolpidem to women by half in 2013.
Why do drugs have sex-specific effects?
One reason is inherent biological sex differences. Women generally have a lower gastric pH and emptying rate, plasma (a blood component) volume, body mass index, lean body mass, organ blood flow, organ sizes and total body water.
There are also variations in the immune system and hormonal reactions between sexes – all of which contribute to disparities in drug metabolism, distribution and absorption.
Lifestyle factors also play a role. Women tend to use more drugs related to reproductive and mental health, which may complicate reactions to other medications.
A population study of over 16 million women and 13.5 million men undergoing medications in the US showed that women took more types of drugs than men (5 vs. 3.7 different medications per year), and women were also less likely to adhere to chronic prescriptions.
So, the higher rates of ADRs in women may be partly a result of increased usage and decreased adherence to medications.
Females underrepresentation in research
Why do current drugs have a strong ADR bias against females? Research shows that the number one reason may be a result of the underrepresentation of females in clinical trials. Therefore, any positive outcomes from a clinical trial may only be applicable to males, and less so in females.
Only as recently as in 1993 did the FDA lift the ban of women of childbearing age to participate in clinical trials. The ban was initially made in 1977 in response to the disaster of thalidomide, a drug to treat pneumonia or nausea during pregnancy, that later caused thousands of birth defects.
Although the ban was revoked, most prescribed drugs today were approved by the FDA before 1993; for example, zolpidem – as discussed above – was approved in 1992. And clinical trials still face the underrepresentation of females.
A machine reading study extracted sex data from 43,135 published reports and 13,165 clinical trials between 1966 and 2018. Analyses unveiled male overrepresentation in seven out of 11 disease categories: HIV/AIDS, chronic kidney diseases, cardiovascular diseases, neoplasms, digestive diseases, neurological disorders, and hepatitis.
Only the musculoskeletal disorders category had female dominance. The remaining three groups – diabetes, mental disorders, and respiratory diseases – had more balanced sex representations.
A research review of 107 clinical trials conducted in the US in 2015 – funded by the National Institutes of Health (NIH) – calculated that 72 per cent of trials did not consider sex as a factor in their analyses. So these trials would not know if the drug(s) of interest had any sex-specific effects.
“When it comes to prescribing drugs, a one-size-fits-all approach, based on male-dominated clinical trials, is not working – and women are getting the short end of the stick,” Professor Zucker noted, adding: “Neglect of females is widespread, even in cell and animal studies where the subjects have been predominantly male.”
I can vouch for this; the majority of neurobiology or brain research used male animals. This is to avoid the confounding effects of hormonal fluctuations in females, we think.
It is not just neurobiology; in fact, “female subjects are underrepresented in animal research across disciplines”, stated a 2018 review in Current Opinion in Behavioural Sciences.
However, such an assumption is unfounded, and the review title speaks for itself: “Inclusion of females does not increase variability in rodent research studies.”
Is lowering drug dosage the answer?
“The common practice of prescribing equal drug doses to women and men neglects sex differences in pharmacokinetics and dimorphisms in body weight, risks overmedication of women, and contributes to female-biased adverse drug reactions,” professors Zucker and Prendergast wrote, adding: “We recommend evidence-based dose reductions for women to counteract this sex bias.”
Lowering drug dosage is a solution, but not an easy one – and this owing to the lack of pharmacokinetic data on women. If the drug becomes useless or not useful enough to relieve symptoms at a lower dosage, then there is no point.
Blindly reducing drug dosage in women is not practical. Any dose limitations must be evidence-based, as the professors said. Finding the lowest safe, effective dose is tricky, which relies on the field of precision dosing.
To sum up: Women are twice as likely to face adverse drug reactions (ADRs) than men at the same dosage, owing to biological and lifestyle differences that affect drug metabolism.
Knowing this, why are most drugs prescribed at the same dose to both sexes? The reason is the underrepresentation of women in clinical trials.
Thus, any clinical results better predict how men respond to the drug and less so about women’s response. On top of that, numerous trials also did not count sex as a factor in their analyses, so data of sex-specific drug reactions for many medications have been lacking.
This makes evidence-based reductions in drug dosage, yet not compromising on efficacy, difficult in women.
- First published in Microbial Instincts. Shin Jie Yong, a published academic author, is a neurobiology postgraduate.