Abstract
Although physiological and hormonal differences between males and females can significantly alter drug absorption, distribution, metabolism, and excretion (ADME), most current pharmacotherapeutic guidelines remain sex neutral. The chapter aims to elucidate biological sex-specific factors across all pharmacokinetic (PK) phases, subsequent therapeutic efficacy, and adverse drug reactions (ADRs), and to highlight implications for individualized therapy including within-woman variation across the menstrual cycle and other hormonal states. This work is based on an extensive review of current literature and clinical data examining sex-specific variations across all phases of pharmacokinetics. Significant biological sex-related differences were found among all PK phases. Females tend to have slower gastric emptying, higher body fat composition, and lower glomerular filtration rates. CYP3A4 is typically more active in females, while CYP1A2, CYP2D6, and CYP2E1 show greater activity in males. In females, endogenous or exogenous hormonal fluctuation can slightly affect gastric motility, protein binding, and selected CYP activities altering clearance for susceptible drugs. In addition, pregnancy increases plasma volume and glomerular filtration with predictable effects on renally cleared drugs and selected hepatic pathways. These differences influence drug half-life, systemic exposure, and the risk of ADRs. Biological sex is a significant determinant of drug pharmacokinetics. Integrating biological sex-specific data into clinical guidelines is essential to optimize drug efficacy and minimize ADRs. Future research and regulatory action should promote biological sex aware pharmacological practices, encouraging routine inclusion of biological sex analyses in clinical trials.