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. 2022 Jun;13(3):559-565.
doi: 10.1007/s41999-021-00587-0. Epub 2021 Nov 19.

Sex-related pharmacokinetic differences with aging

Felix Stader  1   2   3 , Catia Marzolini  4   5
Affiliations

Sex-related pharmacokinetic differences with aging

Felix Stader et al. Eur Geriatr Med. 2022 Jun.

Abstract

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 (Cmax) (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 (tmax), apparent volume of distribution (VdF) and elimination half-life (t1/2) were not significantly different. Body weight and the drug main elimination pathway contributed to sex-related differences in Cmax and AUC. Relative to men, women had a modest increase in Cmax 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 Cmax, 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.

Keywords: Ageing; Pharmacokinetics; Sex.

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References

    1. Soldin OP, Mattison DR (2009) Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 48:143–157 - DOI
    1. Stader F, Siccardi M, Battegay M, Kinvig H, Penny MA, Marzolini C (2019) Repository describing an aging population to inform physiologically based pharmacokinetic models considering anatomical, physiological, and biological age-dependent changes. Clin Pharmacokinet 58:483–501 - DOI
    1. Chetty M, Mattison D, Rostami-Hodjegan A (2012) Sex differences in the clearance of CYP3A4 substrates: exploring possible reasons for the substrate dependency and lack of consensus. Curr Drug Metab 13:778–786 - DOI
    1. Stader F, Courlet P, Kinvig H, Battegay M, Decosterd LA, Penny MA, Siccardi M, Marzolini C (2020) Effect of ageing in antiretroviral drug pharmacokinetics using clinical data combined with modelling and simulation. Br J Clin Pharmacol 87:458–470 - DOI
    1. Stader F, Kinvig H, Penny MA, Battegay M, Siccardi M, Marzolini C (2020) Physiologically based pharmacokinetic modelling to identify pharmackokinetic parameters driving drug exposure changes in the elderly. Clin Pharmacokinet 59:383–401 - DOI

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