Sex differences in the pharmacokinetics of anticancer drugs: a systematic review

J Delahousse; A D Wagner; S Borchmann; A A Adjei; J Haanen; F Burgers; A Letsch; A Quaas; S Oertelt-Prigione; B C Özdemir; R H A Verhoeven; O Della Pasqua; A Paci; O Mir

doi:10.1016/j.esmoop.2024.104002

Sex differences in the pharmacokinetics of anticancer drugs: a systematic review

ESMO Open. 2024 Dec;9(12):104002. doi: 10.1016/j.esmoop.2024.104002. Epub 2024 Dec 10.

Authors

J Delahousse¹, A D Wagner², S Borchmann³, A A Adjei⁴, J Haanen⁵, F Burgers⁶, A Letsch⁷, A Quaas⁸, S Oertelt-Prigione⁹, B C Özdemir¹⁰, R H A Verhoeven¹¹, O Della Pasqua¹², A Paci¹³, O Mir¹

Affiliations

¹ Department of Pharmacology, Gustave Roussy, Villejuif, France.
² Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. Electronic address: [email protected].
³ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany; Cancer Center Cologne Essen (CCCE), Cologne, Germany; German Hodgkin Study Group, Cologne, Germany.
⁴ Taussig Cancer Center, Cleveland Clinic, Cleveland, USA.
⁵ Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands; Melanoma Clinic, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁶ Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.
⁷ Department of Hematology and Oncology, University Hospital Schleswig Holstein/University Cancer Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
⁸ Institute of Pathology, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
⁹ Gender Unit, Department of Primary and Community Care, Radboud University Medical Center, Nijmegen, Netherlands; AG10 Sex- and Gender-Sensitive Medicine, Medical Faculty OWL, University of Bielefeld, Bielefeld, Germany.
¹⁰ Department of Medical Oncology, Bern University Hospital, Bern, Switzerland.
¹¹ Department of Research & Development, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, Netherlands; Department of Medical Oncology, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands; Cancer Center Amsterdam, Cancer Treatment and Quality of Life, Amsterdam, Netherlands.
¹² Clinical Pharmacology & Therapeutics Group, University College London, London, UK.
¹³ Department of Pharmacology, Gustave Roussy, Villejuif, France; Pharmacokinetics Department, Faculté de Pharmacie, Université Paris-Saclay, Gif-sur-Yvette, France.

PMID: 39662226
DOI: 10.1016/j.esmoop.2024.104002

Abstract

Background: In addition to the effect of body weight, a patient's sex can influence the pharmacokinetics (PK) of anticancer agents, and thereby their activity and safety. The magnitude and relevance of sex differences, however, are currently unclear.

Methods: We carried out a systematic review of published studies (clinical, n ≥ 10) on Food and Drug Administration (FDA)-approved (on 31 January 2022) anticancer drugs (excluding hormonal agents), aiming to identify significant PK differences between male and female patients. A difference of ≥20% on PK parameters (clearance or trough concentration) was considered significant. The methodological quality was assessed using the National Institutes of Health study quality assessment tool. This systematic review was conducted according to the PRISMA2020 guidelines and a previously published protocol, which was registered in the PROSPERO database (number 291008).

Results: Data on 99 anticancer agents (for a total of 1643 abstracts and European Medicines Agency/FDA documents) were screened. The final dataset included 112 articles and 8 European Medicines Agency/FDA documents. The median size of a study cohort was 445 patients (range: 12-6468 patients). Significant PK differences (>+20% in clearance or apparent clearance in women) were identified for 14 drugs, and potentially significant PK differences (due to conflicting reports) for another 8 drugs. None of the studies included sex-based summaries to assess whether the observed differences in PK may impact the efficacy or safety profile.

Conclusions: Significant sex differences in PK have been identified including commonly used drugs of different classes, such as 5-fluorouracil, doxorubicin, paclitaxel, regorafenib, atezolizumab, and temozolomide. The risk-benefit ratio for such anticancer drugs is likely to be improved by the development of sex-specific dosing strategies. Additional sex-based PK-pharmacodynamic analyses are recommended during dose optimisation and are to be conducted in line with the FDA Project Optimus guidance. They should be reported even if no association between the patients' sex and the activity and/or toxicity of an anticancer drug has been identified.

Keywords: antineoplastic agents; gender medicine; pharmacokinetics; population pharmacokinetics; sex.

Publication types

Systematic Review

MeSH terms

Antineoplastic Agents* / pharmacokinetics
Antineoplastic Agents* / pharmacology
Female
Humans
Male
Neoplasms / drug therapy
Sex Characteristics
Sex Factors

Substances

Antineoplastic Agents