Sally Babiker1, Alessandro Di Deo1, Elsa Smith1, Anna Dorothea Wagner2, Oscar Della Pasqua1
1Clinical Pharmacology & Therapeutics Group, University College London, 2Department of Oncology, University Hospital of Lausanne
Introduction: In oncology, male and female patients have historically been treated as equals. Consequently, sex-based differences in treatment effects have widely been overlooked[1]. Studies have demonstrated that females exhibit higher susceptibility to drug-related toxicity than males, even after adjusting for differences in body weight. For instance, females with colorectal cancer treated with fluorouracil exhibit an increased risk of gastrointestinal side effects[2,3]. Studies have also shown a link between drug exposure and adverse events; in breast cancer patients, higher paclitaxel (PTX) exposure was predictive of treatment-limiting neuropathy[4]. Despite these relationships, potential differences between males and females remain underexplored. This is important, as multiple underlying factors have been proposed to explain these discrepancies, including that sex differences may affect drug pharmacokinetics (PK), resulting in higher systemic drug exposure in females[2,5]. Nonetheless, approved regimens largely rely on BSA, which does not accurately describe interindividual differences in disposition characteristics of many oncological compounds[6]. Hence, in line with the European Oncologic Society’s efforts towards treatment personalisation, this study aimed to investigate the differences in exposure and safety profile of male and female patients affected by colorectal cancer receiving PTX, doxorubicin (DXR), and 5- fluorouracil (5-FU) in order to inform dosing recommendations. Methods: A literature review was performed for each drug in order to identify suitable PK models which were then re-assessed to explore the implications of sex on drug disposition [7-9]. All models included BSA as a covariate, while the PTX model also included sex as a covariate. Kinetics were then extrapolated, with the effect of BSA-based allometry incorporated in all models to describe size differences. The analyses focused on newly diagnosed subjects during the initial induction cycle for all drugs. A virtual adult population of 5,000 subjects (2,500 females and 2,500 males) was generated using data from the NHANES database. Simulated regimens included: PTX: 175 mg/m² IV over 3h, q3w. DXR: 60 mg/m² IV bolus over 6 min, day 1 of q21d cycle × 4 cycles. 5-FU: 400 mg/m² IV bolus (day 1), then 2,400–3,000 mg/m² IV infusion over 46h, q2w. Predicted AUC and Cmax were used as metrics of exposure. In order to assess the difference between sexes, the percentage (%) of female versus male subjects with predicted AUC and Cmax values above the predicted 75th percentile was compared across all drugs. Results: Baseline characteristics of the male and female population used as the virtual cohort in the simulation scenarios were: for males, median (range) age of 49 (18–80) years, weight of 81.6 (42.9–110) kg, BSA of 2 (1.4–2.4) m², and total bilirubin of 12 (0.2–20.5) µmol/L; and for females, median (range) age of 46 (18–80) years, weight of 70 (40–110) kg, BSA of 1.8 (1.3–2.3) m², and total bilirubin of 8.6 (0.9–20.5) µmol/L. Standard statistical summaries, including medians and 90% confidence intervals, did not seem to capture differences in exposure and safety profile for the drugs of interest. For the approved PTX regimen, AUC and Cmax values above the 75th percentile of the exposure distribution (i.e. AUC = 15.5 µmol/L.h, Cmax = 4.4 µmol/L) were observed, respectively, in 15.4% and 10.3% more female patients than males. For the approved DXR regimen, the same metrics (i.e. AUC = 1385 µg/L.h, Cmax = 1907 µg/L) revealed that there were 7% and 4.4.% more females than males. Simulations of the approved 5-FU regimen showed smaller differences in systemic exposure between males and females. Conclusions: Our findings show that the use of currently approved dosing regimens of PTX and DXR results in a significantly larger proportion of female subjects being exposed to high drug levels compared to males. Given the established evidence of increased susceptibility to drug-related toxicity, this study suggests that differences in systemic exposure between females and males is a contributing factor to the disparities seen in adverse event incidence reported in the literature. Notably, our analysis describes the effect of monotherapy, whereas these drugs are routinely given in combination regimens. Hence, it can be anticipated that sex-related differences may be magnified following the use of combination regimens.
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Reference: PAGE 33 (2025) Abstr 11327 [www.page-meeting.org/?abstract=11327]
Poster: Drug/Disease Modelling - Oncology