Delahousse J, Wagner A D, Borchmann S, Adjei A A, Haanen J, Burgers F, Letsch A, Quaas A, Oertelt-Prigione S, Özdemir B C, Verhoeven R H A, Della Pasqua O, Paci A, Mir O
Department of Pharmacology, Gustave Roussy, Villejuif, France.
Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
ESMO Open. 2024 Dec;9(12):104002. doi: 10.1016/j.esmoop.2024.104002. Epub 2024 Dec 10.
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.
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).
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.
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.
除体重影响外，患者性别可影响抗癌药物的药代动力学（PK），进而影响其活性和安全性。然而，性别差异的程度和相关性目前尚不清楚。
我们对已发表的研究（临床研究，n≥10）进行了系统评价，这些研究涉及美国食品药品监督管理局（FDA）于2022年1月31日批准的抗癌药物（不包括激素类药物），旨在确定男性和女性患者之间显著的PK差异。PK参数（清除率或谷浓度）相差≥20%被认为具有显著性。使用美国国立卫生研究院研究质量评估工具评估方法学质量。本系统评价按照PRISMA2020指南和先前发表的方案进行，该方案已在PROSPERO数据库中注册（编号291008）。
筛选了99种抗癌药物的数据（共1643篇摘要和欧洲药品管理局/FDA文件）。最终数据集包括112篇文章和8份欧洲药品管理局/FDA文件。研究队列的中位数规模为445名患者（范围：12 - 6468名患者）。确定了14种药物存在显著的PK差异（女性清除率或表观清除率>+20%），另外8种药物存在潜在显著的PK差异（由于报告相互矛盾）。没有一项研究包括基于性别的总结，以评估观察到的PK差异是否可能影响疗效或安全性。
已确定PK存在显著的性别差异，包括不同类别的常用药物，如5-氟尿嘧啶、多柔比星、紫杉醇、瑞戈非尼、阿替利珠单抗和替莫唑胺。通过制定针对性别的给药策略，此类抗癌药物的风险效益比可能会得到改善。建议在剂量优化期间进行额外的基于性别的PK-药效学分析，并应按照FDA的Optimus项目指南进行。即使未发现患者性别与抗癌药物活性和/或毒性之间存在关联，也应报告这些分析结果。
