Importance of sex-dependent differences for dosing selection and optimization of chemotherapeutic drugs.

Abstract

Background Despite major advances in cancer treatment in the past years, there is a need to optimize chemotherapeutic drugs dosing strategies to reduce toxicities, suboptimal responses, and the risk of relapse. Most cancer drugs have a narrow therapeutic index with substantial pharmacokinetics variability. Yet, current dosing approaches do not fully account for the complex pathophysiological characteristics of the patients. In this regard, the effect of sex on anticancer chemotherapeutic drugs disposition is still underexplored. In this article, we review sex differences in chemotherapeutic drug pharmacokinetics, we suggest a novel approach that integrates sex into the traditional a priori body-surface-area (BSA) dosing selection model and finally, we provide an overview of the potential benefits of a broader use of therapeutic drug monitoring (TDM) in oncology. Summary To date, anticancer chemotherapeutic drugs dosing is most often determined by BSA, a method widely used for of its ease-of-practice, despite criticism for not accounting for individual factors, notably sex. Anatomical, physiological, and biological differences between males and females can affect pharmacokinetics, including drug metabolism and clearance. At equivalent doses, females tend to display higher circulating exposure and more organ toxicities, which has been formally demonstrated at present for about 20% of chemotherapeutic drugs. An alternative could be the Sex-Adjusted-BSA (SA-BSA), incorporating a 10% increase in dosing for males and a 10% decrease for females, though this approach still lacks formal clinical validation. Another strategy to reduce treatment-related toxicity and potentially enhance clinical outcomes could be a more widespread use of therapeutic drug monitoring (TDM), for which a benefit has been demonstrated for 5-fluorouracil, busulfan, methotrexate or thiopurines.