Drug Trials on Venus & Mars: The role of Sex in Drug Efficacy and Safety
Men and women have clear internal and external differences - males tend to be taller, have more testosterone and contain the XY chromosomes while women tend to live longer, have more estrogen and contain XX chromosomes. For much of the 20th century, however, clinical trials to evaluate the safety and effectiveness of drugs were almost exclusively conducted in males. This relied upon the assumption males were the “average” and females would only introduce unnecessary costs, risks and complications. Only in the early 1990s did leading organisations like the National Institutes of Health in the USA recommend women should be included in clinical trials. There is even less research involving transgender individuals, despite uncertainty around the potential effects of gender-affirming hormone therapies on drug efficacy or safety.
SEX AND DRUG DOSAGES
Pharmacokinetics is used to quantify how a drug interacts with patients; if a drug takes longer to leave the body, or moves into other tissues like fat, the concentrations reaching target tissues will be lower. Pharmacokinetic information for established drugs is scarce, and it is even rarer for sex-specific pharmacokinetic values to be presented. Various factors can affect the pharmacokinetics of a drug, and many of these factors differ notably between sexes. The rate of blood filtration by the kidneys, affecting how fast drugs are excreted from the body, tend to be lower in females. Women also have smaller volumes of plasma than men, and are generally smaller. They also have a higher percentage of fat which is notable as some drugs, such as anaesthetics, preferentially distribute into fat, allowing concentrations to build up. Some studies also show differences in the expression and activity of key enzymes involved in the processing of drugs such as Cytochrome P450.
A recent study by Zucker and Prendergast1 looked at the sex-specific pharmacokinetics and adverse effects of over 80 FDA-approved drugs, and noted that there were significant differences in pharmacokinetics for the majority of these drugs between males and females. They found women took longer to eliminate most drugs with higher drug concentrations in their blood. This was associated with higher incidence of adverse effects in women, implying relatively higher doses in females is associated with harm. However, as patient blood concentrations were not matched with outcomes, it is not possible to confirm causation. It is also worth noting though that adverse effects, whether mild headaches or events requiring hospitalisation, are as much as twice as common in females overall; might this be due to relative overdosage in females?
ROLE OF THE MENSTRUAL CYCLE
One of the justifications for exclusion of females from clinical trials has been the complication contributed by the periodic variation in sex hormones over weeks due to the menstrual cycle. Yet in practice, menstruation and drugs do have to interact, and it is important to understand how fluctuating hormone levels might impact how drugs work. Most studies don’t consider this factor, and may not even distinguish between women on or off hormonal contraceptives. A 2018 study measured over 400 metabolites, vitamins, minerals and other parameters in the urine and blood of 34 healthy women across four time points during a single menstrual cycle1. They found notable variation in levels of amino acids (component parts of proteins), and signs fat utilisation may also vary with cycle. This is a small and low-resolution study, but it demonstrates the biochemical variation across the menstrual cycle, which could have implications for the action of drugs.
A particularly lacking area of research into drug efficacy and safety is pregnancy. Understandably, there is significant trepidation about including pregnant females, due to the potential harm to both foetus and mother. However, by not including pregnancy in clinical trials, we are left without an evidence base for whether it is safe to use even some of the commonest drugs during pregnancy, both given the physiological changes for the mother, and the healthy development of the foetus. For example, paracetamol, a common painkiller, is used during over half of all pregnancies worldwide and is listed in the BNF (British National Formulary) - a database commonly used by medical professionals when prescribing various drugs - as “not known to be harmful”. However, the European Medicines Agency and FDA have both failed to find conclusive data to confidently state whether or not it is safe to use during pregnancy. A recent review conducted by an expert panel considered observational studies in humans alongside studies in rodents, concluding that there were concerning associations between paracetamol use and genital malformations or developmental disorders1.
Clearly, it is important to conduct trials during pregnancy to make decisions about drug safety, even for well-established drugs like paracetamol. However, the challenges of including pregnant women in clinical trials is compounded by the lack of adequate animal or cell models of pregnancy to preliminarily gauge drug toxicity. There are key differences between humans and other mammals in terms of placental structure and foetal development, neither of which are easily modelled with isolated cells. Drugs that are toxic in pregnant rodents may not be toxic in pregnant humans, or even in other mammals, and similarly drugs that aren’t toxic in these models may prove to be harmful in pregnant humans. This might also vary with the stage of pregnancy. Unfortunately, not conducting clinical trials in pregnant individuals simply moves the burden of risk to clinical practice.
SAFE DRUGS ON VENUS
Clearly, the historical legacy of excluding females, particularly pregnant ones, from trials lingers on in uncertainties in the appropriateness of drug usage and dosage in females. We are now including females in trials but further improvements must be made. Routine inclusion of male and female cells or animals in drug trials as well as sex-specific data analysis in clinical trials would both be useful. In lieu of this data, the next best action for medical professionals, for select drugs and conditions, might be to start females on a lower dosage and increase it if it should fail to be effective at that dosage. With these measures, there is potential to finally take into account one of the most fundamental levels of personalisation in medicine.