Different genders respond to drugs differently. For this we need an approach that is attentive to differences, despite the slow progress towards a more inclusive experimentation.
On the one hand it helped to sleep better, on the other hand it stayed around for too long, so much so that the next morning the risk of being involved in a car accident on the way to work was very high. His name is zolpidem, active ingredient in widely prescribed drugs forinsomnia and no, it is no coincidence that the sentence refers to women (and not men) behind the wheel. It is in fact also thanks to episodes of reduced ability to drive in women who took the drug that a few years ago the Fda (or Food & drug administration), the US regulatory body that regulates the use of medicines, has come to recommend from reduce the dosage to women, after having ascertained that the they metabolize much slower than men.
How is it possible that all this happened after more than twenty years that the medicine was on the market? “They are the consequences of how the drug testing, all focused both in the preclinical phase – that is, that of the laboratory and on animals – both in the clinical phase – that is the one about the human being – focused on a single model: the male one “. To answer, on the occasion of the latest edition of Trieste Next, And Silvia From France, researcher at the University of Turin and expert in gender pharmacology, a transversal approach of medical science that investigates the efficacy and safety profile of drugs taking into account the differences defined by sex and gender. Differences that permeate the entire history of medicine, reach up to the present day, those of the pandemic of Covid-19, and which De Francia has recently summarized in the book The medicine of differences – Stories of women, men and discrimination (Neos Edizioni).
A series of bad stories
That of zolpidem is (unfortunately) neither unique nor rare. Dwelling on even the most striking examples, we can rewind the tape back to 1950s and 1960s, where the failure to include women in the evaluation of an anti-nausea drug, the thalidomide, very used at the time to counteract the disorder during pregnancy, caused a real health disaster. Since its release on the market in Europe there were over 12 thousand children born without or with very serious malformations of the limbs and many spontaneous abortions before it came to light which, if taken during the first trimester of pregnancy, had an effect teratogeno. “The drug had not been tested on pregnant rats before it was indicated for use on pregnant women: the tests were only conducted retrospectively “, comments De Francia. Ten years earlier that had been the case with dietilstilbestrolo, a hormonal drug at the time it took to prevent abortion but he revealed serious consequences on offspring, such as genital malformations and carcinomas.
The first reporting on the gender difference in pharmacology concerns the effects “Unbalanced” of barbiturates in animal models and even dates back to 1932. “Nevertheless, the first steps towards a reform of research and clinical practice in this perspective date back only to the end of the last century”, says De Francia. We have to wait for the 1993 for the FDA to include the obligation to recruitment of both genders, with repercussions on new medicines put on the market in fact starting from late nineties. Until that time the only reference for clinical research was the white male, young, about 70 kilos of weight.
Today, almost 90 years after the first evidence of this need, there is an enrollment of the female model between 20 and 25%. “In short, equality is still a long way off”, comments the researcher.
Why this gender bias
For a long time, medical science has been based on the assumption that men and women, except for i characters related to reproduction, were the same. “Beyond this, the exclusion of women from research simplifies, and a lot, the analysis”, explains De Francia: “The female organism is more complex and more difficult to manage from the point of view of returning results”. Let’s think, for example, of how it changes over time, and therefore in different ones age group, from fertile period up to menopause, passing through a pregnancy and thefeeding time, acquiring different characteristics and with the possibility of a different response to treatments based on the hormonal baggage of any specific moment.
“By retrospectively analyzing the drugs already in use for some time also on the female population e tested only on a male sample, we begin to notice the first ones adverse events, the unexpected reactions, already on girls who are entering the period of puberty, as if before, up to 8-10 years, males and females were much, much more similar “, explains De Francia: “From that moment of development the gap becomes enormous, but not only: it is clear that in many cases not only the hormonal baggage conditions the effect of drugs but can, at the same time, be itself influenced by the administration of drugs “.
Different organisms
As well as on the front of the hormonal variability, the male and female bodies also have significant anatomical differences: the latter presents organs (on average) smaller, a different one composition, a different one distribution of fat and lean mass, a different liquid content. All factors that affect both pharmacokinetics (the process by which a drug is transported, absorbed and metabolized by our body) and on pharmacodynamics (which instead concerns the biological and biochemical effects of drugs).
The enzymes with a role in the metabolism of medicines can be expressed differently between men and women, as well as another front to consider is that based on sex and gender people have a different immune response and they suffer from diseases differently. “Women have a more powerful defense system that protects them from viruses, bacteria and even cancer better than men – explains De Francia – and they tend to respond better to vaccines, developing more antibodies “. The price to pay is that, on the other hand, they are much more affected by autoimmune diseases.
360 degree inclusion
To overcome the gender bias and be able to talk about inclusion ed equity it is not enough to think of eliminating the knowledge gap that characterizes research on men and women and indeed, “The need, and the urgency, to study all possible models is increasingly clear”, explains De Francia. We think about people transgender, with respect to which there are practically no studies, but also to the population elderly or the one in pediatric age, also underrepresented. “An eight-year-old child is not a less heavy adult but an individual with different hormonal characteristics and organ maturation”, the researcher goes on: “Nevertheless, therapies for children are very often ‘adjusted’ compared to those of adults and there are very few ad hoc studies”.
Gender, drugs and Covid-19
The pandemic, beyond the catastrophe it has brought about, has provided a big deal driving the gender approach in the clinical trial and pharmacological and it was the first major global health issue where the principles of gender medicine were taken into consideration, also because various supranational agencies have insisted on data collection disaggregated by gender. Nevertheless, there is still a long way to go.
An open front is that of drugs for the treatment of infection. The lack of approved therapies for Covid-19 makes the repurposing, i.e. the reuse or repositioning of old, already approved medicines, a relevant approach. We are talking about drugs already used for other pathologies that have been investigated in recent months, such as for example hydroxychloroquine, anti-inflammatory, antiviral, “For which preclinical and clinical tests, including safety and pharmacokinetic profiles, have been performed in the past, but only on the male model, and which before being tested for treatment against Covid-19 they have not undergone any study with a view to gender differences”, explains De Francia.
“Filling these gaps is one urgent matter”, the researcher goes on: “If in the search for solutions against Covid-19 also the repurposing is conducted in such a way as to strengthen sexual neutrality with the exclusion, once again, of women or other groups of the population, the risk is to exacerbate the health inequalities in the treatments “.