Influence of biological sex-based differences in pharmacology: Implications for drug therapy, safety

Biological sex is an important determinant of drug response; however, clinical pharmacotherapy continues to rely largely on sex-neutral dosing strategies. Historically, drug development and clinical trials have under-represented women, leading to therapeutic recommendations that inadequately account for sex-based physiological and biochemical differences. Growing evidence demonstrates that sex significantly influences pharmacokinetics through variations in gastrointestinal function, body composition, plasma protein binding, hepatic metabolism, and renal elimination. In addition, pharmacodynamic differences related to receptor expression, signal transduction, electrophysiology, immune responses, and pain perception contribute to clinically meaningful differences in drug efficacy and safety between males and females. These variations are particularly relevant for central nervous system drugs, cardiovascular agents, analgesics, antidiabetic therapies, and anticancer drugs. Epidemiological data consistently show a higher incidence of adverse drug reactions in females, highlighting sex as an independent risk factor for drug-related harm. Despite these findings, sex-based considerations remain inadequately integrated into routine prescribing practices and pharmacovigilance systems. In the era of precision medicine, continued reliance on a “one-dose-fits-all” paradigm appears scientifically outdated. This review critically examines the biological basis of sex-based differences in pharmacology, evaluates their clinical implications across major therapeutic classes, and emphasizes the need for incorporation of sex as a biological variable in drug development, clinical trials, dosing strategies, and post-marketing surveillance. Adoption of this approach has the potential to optimize drug therapy and minimize adverse drug outcomes.