https://orcid.org/0000-0002-5970-1501
Context
Older men and women are major users of therapeutic drugs. Indeed, modern medicine, including use of therapeutic drugs, has made a major contribution to the aging of our population. There are sex differences in how the body handles a drug (pharmacokinetics) and in how a drug affects the body (pharmacodynamics). These result in sex differences in the effectiveness and safety of drugs. Sex differences are one of many causes of variability in drug response. When predicting drug effects in older adults, sex (biological) must be considered along with gender (sociocultural), age, genetics, disease, other drugs, and sociodemographic factors (Fujita et al., 2023). It is particularly important to consider the intersection between sex and age effects.
Until recently, there has been very little consideration of the impact of sex differences in research on drugs for older adults. Most preclinical research was performed in cell cultures without considering sex and in male animal models. Clinical research has disproportionately recruited males over females. Consequently, there are limited data on sex differences. Furthermore, there are limited data from older animals and participants in clinical trials are, on average, much younger than real-life users of drugs. There is a need for better data on the impact of sex and age and their intersections on drug effects. Careful evaluation and consideration of sex differences throughout the drug development and use cycle will improve outcomes of therapeutic drugs for older adults.
Sex and Age Differences in How the Body Handles a Drug (Pharmacokinetics)
There are reasonably well-established sex differences in pharmacokinetics (Schwartz, 2007; Soldin & Mattison, 2009). Sex needs to be considered with the intersection of increasing age. Sex differences in body composition and organ function affect absorption, distribution, metabolism, and excretion of drugs. These changes persist beyond menopause. For most drugs, if the same dose is taken by a population of males and females, then on average, the females will have a higher exposure to the drug. Sex is only one of many factors that contributes to variability in pharmacokinetics. In older age, the effects of sex may be relatively small compared with effects of age itself and of diseases and other factors.
Most drugs are taken orally and absorbed through the gastrointestinal tract. The extent of passive absorption across the intestinal mucosa is similar in older males and females. Sex differences in diet may result in different drug–food interactions. There is increasing understanding of sex differences in active transport of drugs, due to differences in expression of transporters such as P-glycoprotein. There is also a reduction in first pass metabolism by the liver in older females, resulting in higher concentrations of the drug reaching the systemic circulation.
Sex differences in drug absorption by other routes and their intersection with age effects are less well defined. It is likely that sex differences in skin (thicker in males, reducing absorption) and in subdermal fat (more in women, may act as a drug depot) affect absorption of topical drugs. Age-related changes in skin structure and function are not thought to have a major impact on drug absorption. Furthermore, sex and age differences in the respiratory tract may affect absorption of inhaled drugs. Males have better respiratory function than females, increasing absorption. The reduction in peak inspiratory flow rate in advancing age means that many older adults cannot generate enough inspiratory effort to absorb drugs administered by dry powder inhaler. The intersection between age and sex factors limits respiratory drug absorption in older females.
Distribution of drugs in the body is affected by body size and composition, which are affected by sex and age. On average, females are smaller than males with relatively less muscle (body water) and more fat, and these differences persist beyond menopause. With advancing age, there is an increase in sarcopenia among both sexes, which is associated with hormone levels and body mass index (Iannuzzi-Sucich et al., 2002). Consequently, females are likely to have higher concentrations of water-soluble drugs and longer half-lives of fat-soluble drugs than males. These features are intensified by the additional physiological changes of aging and frailty.
Most drugs are predominantly metabolized by liver enzymes. Some enzymes have higher activity in females than males, and others are more active in males than in females. Therefore, the effects of sex on drug clearance varies between drugs depending on their metabolic pathways. Much of the variability in enzyme activity is attributed to response to sex hormones. Sex differences in sex hormone levels persist (to a lesser degree) even after menopause. Some sex differences in metabolism seen in preclinical models are not consistent with human drug metabolism. Therefore, it is important to evaluate sex differences in drug metabolism in clinical studies. Aging also differentially affects the activity of different liver enzymes, resulting in age–sex interactions. Drug metabolism by the liver is affected by drug interactions, where drugs can induce (increase) or inhibit (block) enzyme function. Therefore, drug metabolism is affected not only by physiological changes in sex and age but also by different patterns of drug use according to sex and age.
Most drug excretion is as water-soluble metabolites by the kidneys. Males have greater renal blood flow, glomerular filtration, tubular secretion, and reabsorption than females and thus have more efficient renal clearance of most drugs. Renal function is reduced in older age. Therefore, older females have particularly poor renal drug clearance, and this needs to be considered in drug dosing and monitoring to avoid toxicity.
Sex and Age Differences in How a Drug Affects the Body (Pharmacodynamics)
The sex differences in drug effects are in part attributable to differences in pharmacokinetics but also to differences in physiology and pathology between males and females. There are sex differences in receptor number, binding, and signal transduction pathways. There are very few data on pharmacodynamic sex differences for many drugs because until recently, these were not routinely or rigorously investigated in preclinical or clinical trials (Franconi & Campesi, 2014). Emerging data highlight important sex and age differences. For example, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are mainstays of treatment for cardiovascular risk factors and disease. These drugs act on the renin–angiotensin system, which is differentially affected by estrogen and testosterone and by aging as well as by genetic polymorphisms. Interactions between these factors may affect drug efficacy. Early findings from preclinical studies of geroscience interventions that target aging itself also show sex differences in response (Carmody et al., 2022).
The intersection between sex and age is prominent in the risk of adverse drug events. Females experience more adverse drug events overall than males (Pirmohamed et al., 2004). Eight of 10 drugs withdrawn from the United States market by the Food and Drug Administration between 1997 and 2000 posed a higher risk to women than men (Heinrich et al., 2001). A major reason for this is the pharmacokinetic changes that result in higher drug exposure in females when they take the same dose as males. Underrepresentation of women in premarketing clinical trials means that adverse drug events in women are less likely to be detected until postmarketing surveillance.
Advancing age also carries an increased risk of adverse drug reactions, particularly of severe adverse drug reactions. Like the increased risk seen in females, this can be attributed to pharmacokinetic changes resulting in increased exposure to drugs and to underrepresentation in clinical trials. In addition, old age and the accompanying multimorbidity increase vulnerability to external stressors. Therefore, the same adverse drug effect will have a bigger impact on an older person. For example, benzodiazepines (sedatives) impair balance, which can make a middle-aged person feel unsteady but make an older person fall. Older females have a higher prevalence of osteoporosis, so are more likely to sustain a fracture after falling than older males.
Interestingly, some types of adverse drug reaction are more common in females and others in males. For example, drug-induced prolongation of the QT interval on the electrocardiogram, which increases the risk of Torsades des Pointes, a dangerous cardiac arrhythmia, is more common in females than males. This can be explained by sex differences in expression of potassium ion channel proteins. Females are also more likely than males to bleed from antiplatelets and anticoagulants and are more likely to develop electrolyte abnormalities with antihypertensives. In the case of antipsychotic drugs, females are more likely than males to experience metabolic syndrome, whereas males are more likely than females to experience extrapyramidal signs, reflecting sex differences in sensitivity to different drug effects.
It is also important to consider the risk of adverse drug reactions in the context of the drug utilization issues outlined below. Female sex and older age are both risk factors for use of multiple drug therapies referred to as polypharmacy, and polypharmacy is the strongest risk factor for adverse drug reactions.
Sex Differences in Drug Use
The sex (biological) differences in drug use can be difficult to disentangle from gender-related sociocultural issues. Overall, females tend to use more drugs than males, and this holds true in older adults, for both prescription medicines and dietary supplements (Manteuffel et al., 2014; Qato et al., 2016). Polypharmacy, generally considered to be the use of five or more drug therapies, is most common in older females, and this carries risks of drug interactions and adverse drug reactions. Female patients are less likely to be adherent with diabetes and cardiovascular medications than males and are less likely to receive guideline-recommended treatment and monitoring (Manteuffel et al., 2014). Although this could represent sex differences in morbidity that may in themselves be attributable to gender issues, it also reflects different patterns of reporting of symptoms, health care use, and clinician gender biases.
Strategies and Policy Opportunities
There is a need to consider sex at every stage of research to improve understanding of variability in drug effects (Figure 1). This will inform drug use and improve outcomes. Although sex is only one of many factors influencing drug response, it is particularly important to consider in geriatric pharmacotherapy, when age and the accompanying multimorbidity increase vulnerability and complexity.
Sex and age differences in geriatric pharmacotherapy: issues and strategies.
Funding incentives and regulation can support generation of data on sex differences in drug effects. Research involving both sexes has been encouraged through funding initiatives, such as the National Institutes of Health (NIH) mandate to include sex as a biological variable in NIH-funded preclinical research, with similar initiatives internationally (Carmody et al., 2022). These initiatives are well beyond incentives to include aged animals. The next frontiers are incentives to study preclinical models that can investigate sex and age effects. Regulatory initiatives such as the recent requirement for representative enrollment in clinical trials in the United States (Consolidated Appropriations Act, 2023) will ensure that drugs are evaluated in people who are representative of those likely to use the drugs. This applies not only to sex but also to age, ethnicity, and other attributes that determine drug response.
Not only is it important to ensure that older females are included in clinical research, it is also important to ensure that these data are subsequently reported. For example, Alzheimer’s disease is a condition that increases with age and is more common in women than men. Recent clinical trial data suggest that drug efficacy may be affected by sex (Buckley et al., 2023). Yet sex and age disaggregated analyses that could be helpful for tailoring therapies to older women and men are not routinely provided (Li & Mason, n.d.). It is important that researchers collect and analyze data to allow for sex and age disaggregation.
The importance of considering the data that emerge on sex differences can be embedded in guidelines, clinical care, and public health interventions. Guideline format could routinely include sections on sex effects as well as intersection with age. The many tools for assessment of prescribing appropriateness in older age could explicitly consider sex effects (Rochon et al., 2021). Clinician education and point-of-care resources could emphasize sex (and age) considerations for drug selection, dosing, and monitoring of effectiveness and safety. Public health campaigns can raise awareness of the impact of sex on drug use.
Older men and women are major users of therapeutic drugs and potentially have a lot to gain with a high prevalence of disease, but they also have a lot to lose with vulnerability to adverse effects. The effects of sex and age on pharmacokinetics, pharmacodynamics, and drug use put older females at particularly high risk of using drugs with limited evidence of benefit and high risk of harm in people like them. Better understanding and reporting of sex and age effects will lead to better outcomes from pharmacological treatment in all older adults.
Better understanding and reporting of sex and age effects will lead to better outcomes from pharmacological treatment in all older adults.
Funding
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Conflict of Interest
None.
