Sex differences on multikinase inhibitors toxicity in patients with advanced gastroenteropancreatic neuroendocrine tumours

Hernando, Jorge; Roca-Herrera, Maria; García-Álvarez, Alejandro; Raymond, Éric; Ruszniewski, Philippe; Kulke, Matthew H.; Grande, Enrique; García‐Carbonero, Rocío; Castellano, Daniel; Salazar, Ramón; Ibrahim, Toni; Teulé, Àlex; Alonso, Vicente; Fazio, Nicola; Valle, Juan W.; Tafuto, Salvatore; Carmona, Ana T.; Navarro, Vı́ctor; Capdevila, Jaume

doi:10.1016/j.ejca.2023.04.013

Cited by 7 publications

(1 citation statement)

References 31 publications

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“…Model simulations showed a significant difference in concentrations between men and women due to the difference in FFM between the two groups [ 49 ]. These results are consistent with clinical practice, which shows a better response to treatment but also more toxicity in women [ 56 , 57 ]. A comparable percentage of women and men achieved the target concentration using 1.5 mg and 2 mg daily respectively.…”

Section: Discussionsupporting

confidence: 90%

Population Pharmacokinetics of Trametinib and Impact of Nonadherence on Drug Exposure in Oncology Patients as Part of the Optimizing Oral Targeted Anticancer Therapies Study

Ravix,

Bandiera,

Cardoso

et al. 2024

Cancers

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Trametinib is a targeted therapy used for the treatment of solid tumours, with significant variability reported in real-life studies. This variability increases the risk of suboptimal exposure, which can lead to treatment failure or increased toxicity. Using model-based simulation, this study aims to characterize and investigate the pharmacokinetics and the adequacy of the currently recommended doses of trametinib. Additionally, the simulation of various suboptimal adherence scenarios allowed for an assessment of the impact of patients’ drug adherence on the treatment outcome. The population data collected in 33 adult patients, providing 113 plasmatic trametinib concentrations, were best described by a two-compartment model with linear absorption and elimination. The study also identified a significant positive effect of fat-free mass and a negative effect of age on clearance, explaining 66% and 21% of the initial associated variability, respectively. Simulations showed that a maximum dose of 2 mg daily achieved the therapeutic target in 36% of male patients compared to 72% of female patients. A dose of 1.5 mg per day in patients over 65 years of age achieved similar rates, with 44% and 79% for male and female patients, respectively, reaching the therapeutic target. Poor adherence leads to a significant drop in concentrations and a high risk of subtherapeutic drug levels. These results underline the importance of interprofessional collaboration and patient partnership along the patient’s journey to address patients’ needs regarding trametinib and support medication adherence.

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Section: Discussionsupporting

confidence: 90%