Addressing sex differences in drug responses: an International Women’s Day interview with Sarah Allegra

Written by Sarah Allegra (San Luigi Gonzaga University Hospital)
Awareness Clinical Drug development Interviews Toxicology

Author: Sarah Allegra, Laboratory of Clinical Pharmacology ‘Franco Ghezzo’, San Luigi Gonzaga University Hospital (Turin, Italy)

Dr Allegra works in the Laboratory of Clinical Pharmacology ‘Franco Ghezzo’ at the San Luigi Gonzaga University Hospital (Turin, Italy), a tertiary referral centre for patients with adrenal diseases and endocrine tumours. Her research program is focused on sex and gender pharmacology, pharmacokinetics and pharmacogenetics of different drugs, such as iron chelating agents, antifungals, antiepileptics, glycopeptides, antiarrhythmics and, in particular, chemotherapeutic agents. Dr Allegra also works on the development and validation of chromatographic methods for the quantification of different analytes in plasma, cells, dry sample spot devices and different biological matrices. Dr Allegra recently co-authored a patent for the development and the validation of a chromatographic kit for the quantification of glyphosate and AMPA in biological matrices. From March 2018 to February 2019 prior to working at the San Luigi Gonzaga University Hospital, she worked in the Laboratory of Immunohistochemistry and Molecular Genetics of the Humanitas Clinical and Research Center (Milan, Italy) with the following responsibilities: to prepare microscopic tissue samples, to stain tissue samples (immunohistochemical analyses) and to conduct and document histology-related projects.

Dr Allegra has authored more than 60 peer-reviewed research papers, 40 of which as first author, reaching an h-index of 15 in the last 10 years. These papers were mostly focused on pharmacology and personalized medicine, as well as her participation at national and international congresses. Dr Allegra also collaborates with the Medical Oncology Unit of the Molinette Hospital (Turin, Italy) and with the Centro Oncologico Ematologico Subalpino (also at the Molinette Hospital) for studies on gender-differences in chemotherapy-related toxicity in patients with diagnosed colorectal, pancreatic and lung cancer. Additionally, she also worked with the Pediatric Hospital of Padua (Padua, Italy), where she routinely performed pharmacokinetic analysis for the evaluation of tyrosine kinase inhibitor concentrations in the plasma and liquor samples of paediatric patients with oncoematological diseases.

1. Sex and gender pharmacology is typically an underfunded and overlooked field of research – what inspired you pursue a career in this area?

Including both sexes is a legitimate strategy to increase heterogeneity.  Sex bias may lead to replication issues if researchers do not reveal the studied sex, which means sex remains an uncontrolled variable during the experiment. Researchers also often neglect to account for sex during a study when sex is a significant source of variance. The way that women’s cells work differs from that of men’s, which influences how vulnerable they are to illness and stress.  Their reaction to medication is also affected by this.  All of this inspired me to pursue a career researching gender differences and mechanisms of cell harm, because this research is needed to develop newer and more potent therapeutic strategies. .

2. You recently published an article on sex-specific disparities impacting cancer chemotherapy drug toxicities – what were your main findings?

Age and gender-specific variables need to be given more consideration because drug side effects vary, are patient-specific, and are not always obvious.  The most recent ‘Plan for the application and diffusion of gender medicine’ that was approved in 2019 by the Italian Ministry of Health states that we must be vigilant when monitoring gender-specific side effects of chemotherapeutic medications.  As of right now, there are very few published scientific studies that provide information on the prevalence of gender-specific adverse effects of chemotherapy medications.  In addition to the disparity in monitoring adverse effects, there are notable inequalities at diagnosis.  Therefore, sex-specific evaluations are crucial for determining the best anti-cancer medication regimen.

3. Why do you think women tend to experience more adverse drug reactions than men, and what are the implications for drug safety?

Treatment response varies between men and women, mostly due to physiological, anatomical and hormonal factors.  The response to therapies is influenced by the existence of sex-related variations in the pharmacokinetics and pharmacodynamics of therapeutic agents.  Even though this has been known since 1932, when the first study on gender differences in the pharmacology of barbiturates in rats was published, it was not until the end of the 20th century that the significance of gender pharmacology was fully recognized. The four stages of a medication’s movement through the human body—absorption, distribution, metabolism and excretion—relate to pharmacokinetics. These four phases exhibit notable sex-related differences since they are mostly impacted by age and hormones. Pharmacodynamics on the other hand, investigates the physiological and biochemical effects as well as the mechanism of action of medicinal agents, and shows how this affects our bodies. There are several pharmacodynamic variations based on sex, which are mostly caused by DNA, hormones and environmental factors. Pharmacodynamic differences are more difficult to identify, whereas pharmacokinetic differences are easier to recognize and analyse. However, both should be thoroughly analyzed and examined in the preclinical stage concerning gender disparities, otherwise the clinical phase that follows will be constrained and imprecise.

4. What challenges exist in studying sex differences in clinical studies?

The inclusion of women in clinical trials has revolutionized the drug development process. Despite this, there is still a need for greater representation of women in clinical studies. Though preclinical research establishes the foundation for the ensuing clinical trials, there hasn’t been much improvement in this area. According to a 1993 law presented by the Council for International Organizations of Medical Sciences and accepted by the FDA, women must participate in clinical studies supported by the National Institutes of Health (NIH). Unfortunately, women of ‘child-bearing potential’ were not allowed to participate in clinical studies until this date in 1993; up to that time, no woman had ever been recruited in a clinical experiment. In 2014, the NIH issued a directive to ensure that preclinical research included both male and female subjects. The number of research proposals that considered both sexes then increased significantly (from 26% to 48%) because of a similar program introduced by the Canadian Institute of Health that required responses to questions about gender and sex during the research grant application process. They did point out that experts in biological sciences were the least likely to acknowledge that they had included sex in their research. These findings underscore the potential for policy interventions to combat sex bias. Sadly, not all research is funded through these avenues, and it is still not possible to include both sexes in all research pipelines.

5. Could you share some strategies for addressing these challenges?

Editors of scientific publications should not accept experimental articles that do not report differentiated recruiting by sex. This is a new call to action that needs to be spread as widely as possible.  Scientific societies must have a definite stance on preclinical research, and laws ought to mandate that both public and private preclinical research must be structured inclusively, taking into account both sexes, in every nation on the planet.  If not, the outcome will always be a clinical experiment with shaky underpinnings that is not really applicable to patients’ daily lives.  To further investigate various sex-specific treatment approaches, more research is required that focuses on sex differences in particular fields or illnesses.

6. How do you think the pharmaceutical industry can improve its approach to studying sex differences in drug development?

The X and Y chromosomes are not the only thing that separates males and females.  In preclinical studies, there has been a common, unfounded belief that male and female rodents share similar traits.  In addition to basic physiological characteristics like body weight, lean mass and fat mass, males and females differ in several neuroendocrine, immunological and behavioural aspects that are not related to reproductive behaviours. In addition, sex differences can affect therapy efficacy, symptom progression and illness susceptibility, and many human diseases affect men and women differently. There are well-established sex differences in cardiovascular diseases, autoimmune illnesses, chronic pain and neuropsychiatric disorders, with females generally having greater occurrences of these conditions than males. Inaccurate data reporting that does not take sex into account as a covariate can also occur in several domains. This can include the study design, phenotypes, pharmacokinetics, pharmacodynamic measures or result interpretation. Regarding animal models utilized in pharmaceutical research, sex differences in disease onset and progression have also been observed. When data is broken down by age, it should also be helpful to take sex differences into account. Different life stages might affect a person’s health and reaction to treatment, especially for women. Age and sex should both be taken into account in a preclinical research model that is actually applicable to human reality.

7. Can you discuss how personalized medicine could help address sex differences in drug responses?

Gender gaps are becoming more noticeable in all areas of medicine, particularly medication therapy, even if there aren’t many dedicated research studies focused on resolving them.  Sex is one crucial factor that cannot be disregarded.  To improve drug safety and efficacy, gender pharmacology must constantly be taken into account while modifying therapy.  Recognizing gender differences promotes appropriate medication use and increased health protection for both sexes.  Additional gender research would allow for reporting on variations in the assimilation and response of female organisms in comparison to male organisms, hence revealing potential risks and advantageous effects that may differ between genders.  Furthermore, a better understanding of how gender and sex affect pharmacological action may make it easier to develop ‘tailored’ drugs.

Disclaimer: the opinions expressed are solely those of the author and do not express the views or opinions of Bioanalysis Zone or Taylor & Francis Group.

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