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Everolimus pharmacokinetics and exposure-response relationship in Japanese patients with advanced breast cancer
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Everolimus pharmacokinetics and exposure-response relationship in Japanese patients with advanced breast cancer
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Everolimus pharmacokinetics and exposure-response relationship in Japanese patients with advanced breast cancer
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Journal Article
Everolimus pharmacokinetics and exposure-response relationship in Japanese patients with advanced breast cancer
2022
Overview
Background: Everolimus is one of the key drugs for the treatment of advanced breast cancer. The optimal target concentration range for everolimus therapy in patients with breast cancer has not yet been established. This study aimed to characterize everolimus pharmacokinetics (PK) and determine the relationship between blood concentration and efficacy as well as adverse events in patients with breast cancer. Methods: This was a prospective, observational PK study. Patients receiving everolimus between November 2015 and November 2018 at our hospital were enrolled in this study. The whole blood samples for the everolimus assay were collected at least two weeks after initiation of treatment or the last everolimus dose change. PK parameters were estimated using Bayesian analysis. Statistical differences in everolimus trough concentrations between patient cohorts were assessed using the Mann–Whitney test. Progression-free survival was assessed using the Kaplan-Meier method and the log-rank test. Results: Eighteen patients were enrolled in the study. The median follow-up period was 35 months. The most frequently observed adverse event was stomatitis (all grade 94%). There was high inter-individual variation in PK parameters such as clearance [range: 5.1–21.3 L/h/70 kg and co-efficient of variation (CV): 38.5%] and volume of distribution of the central compartment (range: 9.9–103.6 L/70 kg and CV: 57.8%). The trough concentrations at dose-limiting toxicities were significantly higher than trough concentrations in the absence of these toxicities ( p = 0.0058). Progression-free survival was significantly longer in the 10–20 ng/ml group than in the other groups ( p = 0.0078). Conclusion: This study characterized the everolimus PK parameters in Japanese patients with breast cancer. High everolimus exposure was found to be associated with poor tolerability. Based on our data, trough concentrations in the range of 10–20 ng/ml may be associated with prolonged progression-free survival. Thus, determining the blood concentration of everolimus and subsequent dose adjustments will potentially reduce side effects and enhance the therapeutic effect in Japanese patients with advanced breast cancer.
