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.
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).
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.
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.
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