Gender-Specific Pharmacokinetics and Pharmacodynamics: History
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Women and men respond differently to treatments; this mainly depends on physiological, anatomical, and hormonal characteristics. The existence of the differences in therapeutic agent pharmacokinetics and pharmacodynamics influences the response to treatments.

  • preclinical experimentation
  • pharmacology
  • sex differences

1. Therapeutic Agent Development Is a Significant Challenge

Therapeutic agent development is driven by medical need, disease prevalence, and the likelihood of success. Therapeutic agent candidate selection is an iterative process between chemistry and biology, whose aim is to refine the molecular properties until a compound suitable for advancing to humans is found. It is an expensive, long, and high-risk process which takes from 10 to 15 years, and it is associated with a high attrition rate; 80 to 90% of research projects fail before they ever get tested in humans, and for every therapeutic agent that gains Food and Drug Administration (FDA) approval, more than 1000 were developed but failed. Prior to administration to humans, the pharmacology and biochemistry of the therapeutic agent is established using an extensive range of in vitro and in vivo test procedures during the preclinical studies [1]. Indeed, starting from the study of the medicine effects on cell cultures, the process goes through animal experimentation, ending with its use in the human species in different clinical phases. It is also an FDA regulatory requirement that the therapeutic agent is administered to animals to assess its safety. Later-stage animal testing is also required to assess the carcinogenicity and the effects on the reproductive system. The goal of preclinical studies is to accurately model, in animals, the desired biological effect of a medicine. This allows doctors to predict the treatment outcome in patients, and to identify toxicities associated with a therapeutic agent, with the aim of predicting adverse events in people [2].
There has been a revolution within clinical trials to include females in the research pipeline. However, there has been limited change in the preclinical arena, yet the preclinical research lays the groundwork for the subsequent clinical trials. In 1993, the Council for International Organizations of Medical Sciences proposed a law, approved by the FDA, requiring women to be included in clinical trials funded by the National Institutes of Health (NIH). Women of “child-bearing potential” were indeed excluded from clinical trials until 1993; until 1993, zero women have ever been enrolled in clinical trials. The NIH issued a mandate in 2014 to guarantee that both male and female subjects are represented in preclinical studies [3]. A comparable program by the Canadian Institute of Health that mandated inquiries about sex and gender during the application process for research funding resulted in a marked rise in the number of applications that took into account both the male and female sexes (from 26 to 48%) [4]. They made a point to mention that scientists working in the biological field were the least likely to admit to including sex in their study. 

2. Gender-Specific Pharmacokinetics and Pharmacodynamics

Women and men respond differently to treatments; this mainly depends on physiological, anatomical, and hormonal characteristics. The existence of the differences in therapeutic agent pharmacokinetics and pharmacodynamics influences the response to treatments [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45]. Although this was already known since 1932, the year in which the first study on the gender difference in the pharmacology of barbiturates in rats was reported, full awareness of the relevance of the role of gender pharmacology only came at the end of the last century [16,26,27,46,47]. By pharmacokinetics, we mean the study of the following four phases of a medicine transition in the body: absorption, distribution, metabolism, and elimination. These four stages are primarily influenced by age and hormones, thus showing significant differences related to sex [48]. Sex hormones may interact negatively with drugs and their metabolic pathways through different mechanisms; these include absorption, competition for transporters, competition and/or regulation of expression of drug-metabolizing enzymes and sex steroids, and drug interactions with pharmacodynamics [49]. In females, drug effectiveness and adverse drug reactions may be impacted by variations in endogenous sex steroid hormones that happen naturally during the menstrual cycle, during pregnancy, and during the transition to menopause [50]. Exogenous hormones are additionally used by women as a contraceptive, as a treatment for hot flashes, nocturnal sweats, vaginal dryness, and a number of other conditions. Hence, these hormone therapies could be viewed as both medical treatments and a cause of adverse drug reactions, as well as a modulator of the effects of other medications. In other words, while drug metabolic pathways may have an impact on exogenous hormones used for therapy, exogenous hormones may also have an impact on other drugs via modifying metabolism. There may be variations in how each person reacts to exogenous hormones due to inter-individual variations in metabolic pathway components (pharmacogenetics) [49].
Male reproductive aging does not result in a complete cessation of testosterone production or spermatogenesis, unlike female reproductive aging (menopause) or organic androgen lack in males (caused by diseases of the brain, pituitary, or testes). In fact, the decrease in circulating testosterone levels brought on by aging in and of itself is moderate, and testosterone levels are typically in the low–normal range in men. However, a small percentage of aging men may experience testosterone deficiency, which is influenced by the presence of comorbidities. According to recent research, elderly men who maintain their health and fitness typically keep their serum testosterone levels regular. The terms andropause, viropause, partial androgen deficit in the aging male, and late-onset hypogonadism have all been used to describe age-related low testosterone in men [51]. Additionally, the gonadal axis is suppressed by the use of some medications, including glucocorticoids and opioids [52,53,54]. Considering pharmacogenetics, it has been observed that cells that carry the UGT1A4*1a allele may have decreased clearance of testosterone as compared to those with the *3a allele [55].
Pharmacodynamics, on the other hand, indicates the effect of a therapeutic agent on bodies and studies the biochemical and physiological effects and their mechanism of action. There are numerous pharmacodynamic differences depending on sex, mainly mediated by hormones, genes, and the environment. The primary organ for excreting drug metabolites or parent drug molecules is the kidney. All three of the main renal processes—glomerular filtration, tubular secretion, and tubular reabsorption—show documented sex differences. Men often have a higher renal clearance than women. The hepatic enzyme activity is altered by elevated levels of estrogen and progesterone, which can lead to an increased drug buildup or decreased drug clearance in some cases. Autoimmunity is influenced by prolactin and female steroid hormones [37]. The incidence and severity of autoimmune/inflammatory illnesses are two to ten times higher in females than in males due to the hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes’ regulation of immunity. Females of reproductive age are the ones who typically have autoimmune illnesses. Hormone levels that fluctuate during menstruation, when using oral contraceptives, during pregnancy, or throughout menopause can also affect metabolic alterations. For instance, some asthmatic women experience symptoms that intensify before or during their periods. Intensive physical activity has been linked to an increase in oxidative stress. Oxidative stress has been linked to gender disparities, particularly as people get older. Studies to investigate this have produced contradictory results, despite the fact that sex hormones are thought to have a major role in modifying sex-based differences in pharmacokinetics. Midazolam clearance, for example, which measures the CYP3A4 metabolic activity, did not change during the course of the menstrual cycle [56]; in addition, studies on eletriptan (used to treat migraines) also showed no changes in response to sex or menstrual cycle [57].
While the pharmacokinetic differences are simpler to analyze, the pharmacodynamic differences are more difficult to detect [26]. However, both deserve a worthy study in the preclinical phase in terms of gender differences, or the resulting clinical phase will be limited and approximate.

This entry is adapted from the peer-reviewed paper 10.3390/ph16060786

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