Why are Adverse Drug Reactions Doubled in Women?

Can 3D pharmaceutical printing provide a solution?

According to the scientific literature, adverse drug reactions account for around 7% of all hospital admissions on average. Previous evidence suggests that certain factors predispose adults to adverse drug reactions, including advanced age, liver and renal disease, polypharmacy contributing to drug interactions, and female biological sex.

Interestingly enough, most biomedical preclinical research has been conducted on male cells and on animals under the assumption that the same mechanisms of drug action are applied to females (or humans for that matter).

Over the past half a century, the World Health Organization (WHO) gathered individual case reports on adverse drug reactions from post-marketing surveillance around the world. Analysis of this post-marketing surveillance data indicated that women, especially from puberty onward through their reproductive years, report more adverse drug reactions twice as often when compared with men. Men, however, more frequently experience serious or fatal adverse drug reactions.

This finding emphasizes the need to take biological sex into account when developing new drugs and determining optimal dosage for efficacy and safety. However, to address drug-related disparities between men and women, sex-linked variables in preclinical materials must effectively model the differences between men and women; otherwise, results obtained would be inaccurate both in theory and in actuality.

This concept of more accurate preclinical research leads us to the relevant question of why women experience adverse drug reactions more frequently than men do. It also underscores the need for the direct application of customization of pharmaceuticals for precision medicine tailored to the characteristics of the individual in question.

Body Size

Scientists developed a hypothesis that women tend to be smaller than men in body size, have decreased lean muscle mass and body weight, and have increased body fat percentage, all of which may in turn affect the absorption, distribution, and metabolism of drugs.

Additionally, certain drugs require calculations accounting for body weight to determine the optimal dosage for an individual. The historic fact that preclinical research and many clinical trials have been done primarily on males led to the theory that perhaps women (in general) are overmedicated due to differences in body weight and lean muscle mass.

Recently published studies including a systematic review of the literature by Zucker and Prendergast in 2020 and a mouse model study by Wilson and colleagues in 2022 have disproven this hypothesis.

The systematic review analyzed over 5000 articles studying sex or gender differences related to adverse drug reactions. A multivariate regression analysis of the data from these studies that adjusted for age, body mass index, and a number of prescribed medications revealed a significant and robust effect of female biological sex on adverse drug reactions. In most cases, adjustments for body mass did not change the higher incidence rate of adverse drug reactions among women. This finding suggests that the disparity between men and women when it comes to experiencing adverse drug reactions is not due to body weight at all.

The researchers conducting the murine study reported that “females are not scaled males” after analyzing sex differences in the allometric relationship between body weight and 363 phenotypic traits in male and female mice. Approximately 73% of traits were dimorphic and among these traits, only 42% showed scaling differences between males and females. This suggests that body weight alone is not enough to explain sex differences within phenotypic traits; however, body weight may be useful when considering certain phenotypic traits to determine case-specific, optimal drug dosage.

Factors to Consider in Women

Immunological, hormonal, and pharmacokinetic factors in the context of aging and current medication usage are all important factors to consider when evaluating the reason behind increased adverse drug reactions experienced by women.

Immunological Factors

How strongly the immune system responds to foreign substances such as drugs differs for everyone. Some people have more efficient, functional immune systems compared with others who are immunocompromised or immunosuppressed with medications for specific reasons. Still, others have hyperactive immune systems such as those who experience anaphylaxis to various allergens, which may include drugs.

All of these immunological factors must be considered, especially when prescribing new drugs to anyone, but particularly women. Women tend to demonstrate more pro-inflammatory immune responses compared with men who demonstrate more anti-inflammatory immune responses.

In general, women demonstrate more robust cellular and humoral immune responses to infections or vaccines and also experience a higher incidence of autoimmune diseases than men. Sex hormones have been shown to affect various components of the immune system, causing biological and molecular differences in immune response in men and women.

Immune system responses as well as hormone levels are both altered during pregnancy and exacerbations of immune-based diseases have been demonstrated during specific phases of the menstrual cycle that are accompanied by fluctuations in hormones.

Impact of Hormones on Drug Metabolism

Sex hormones also directly or indirectly affect transporters, receptors, and enzymes involved in drug absorption, distribution, metabolism, and elimination.

The use of hormonal therapies, transgender therapies, contraceptives, and other pharmaceutical treatments must also be considered for an accurate and full picture of the impact of sex hormones on drug pharmacokinetics.

In particular, sex differences have been observed in hospital admissions related to specific drug-adverse drug reaction combinations. Interestingly, women demonstrated an increased likelihood of hospital admission related to the use of diuretics and anticoagulants.

Conclusion

In short, human beings are complicated. Being female complicates things further when considering different hormone levels, immune responses, and pharmacokinetics.

Add genetic variables to the mix. The way each individual’s body processes a drug is unique. Therefore, it is necessary to prescribe and mass produce drugs that are specifically tailored to each individual, taking all of these variables into account to reduce the likelihood of adverse drug reactions, especially in women.

In theory, 3D pharmaceutical printing offers a promising, precision-medicine-based solution to the problem of adverse drug reaction sex disparities. 3D printing allows for rapid, easy execution of formula-based changes in drug dosage, shape, and release profiles, which are truly catered to each individual’s needs.

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Laxxon Medical is dedicated to engineering patented 3D pharmaceutical solutions which optimize products and benefit patients. Our goal is to establish SPID®-Technology as a manufacturing process that has the individual and the pharmaceutical partner in mind.

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