Sex-related pharmacokinetic differences with aging

Key summary pointsAim To evaluate the combined effect of sex- and age-related physiological and biological changes on drug pharmacokinetics. Findings Median peak concentration and drug exposure were on average 22% and 20% higher in women compared with men. With increasing age, sex differences in peak concentration tended to be more pronounced but remained similar for drug exposure. Message The pharmacokinetic differences between women and men are modest and, with the exception of peak concentration, remain constant with increasing age. Purpose The proportion of women increases with advanced age, but older women are often underrepresented in clinical trials. Therefore, little is known about the combined effect of sex- and age-related physiological changes on drug pharmacokinetics. Methods We compiled clinical studies, which investigated sex-related pharmacokinetic differences both in older and young women and men. The ratio women/men was calculated for various pharmacokinetic parameters across adulthood to assess sex-related differences in drug pharmacokinetics with aging. The contribution of body weight and drug characteristics to sex-related pharmacokinetic differences were explored using analysis of variance. Results We found 67 studies reporting the pharmacokinetics for 56 drugs both in older and young women and men. Median peak concentration (C-max) (interquartile range (IQR)) and drug exposure (AUC) (IQR) were 22% (8-41%) and 20% (0-39%) higher in women compared with men whereas time to peak concentration (t(max)), apparent volume of distribution (VdF) and elimination half-life (t(1/2)) were not significantly different. Body weight and the drug main elimination pathway contributed to sex-related differences in C-max and AUC. Relative to men, women had a modest increase in C-max with increasing age (r = 0.19, p = 0.04). Conversely, sex-related differences in AUC remained constant with increasing age. Conclusion The pharmacokinetic differences between women and men were modest and, with the exception of C-max, remained constant with increasing age. The higher plasma concentration might be correlated to more adverse events in older women and thus, drug treatment should be started on the lower recommended dosage when appropriate particularly for drugs characterized by a narrow therapeutic index.