Influence of Enzalutamide on Cabazitaxel Pharmacokinetics: a Drug-Drug Interaction Study in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients.

Autor: Belderbos BPS; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., Bins S; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., van Leeuwen RWF; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.; Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, the Netherlands., Oomen-de Hoop E; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., van der Meer N; Clinical Trial Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., de Bruijn P; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., Hamberg P; Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands., Overkleeft ENM; Department of Internal Medicine, Ikazia Hospital, Rotterdam, the Netherlands., van der Deure WM; Department of Internal Medicine, Groene Hart Hospital, Gouda, the Netherlands., Lolkema MP; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., de Wit R; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., Mathijssen RHJ; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. a.mathijssen@erasmusmc.nl.
Jazyk: angličtina
Zdroj: Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2018 Feb 01; Vol. 24 (3), pp. 541-546. Date of Electronic Publication: 2017 Nov 17.
DOI: 10.1158/1078-0432.CCR-17-2336
Abstrakt: Purpose: In ongoing clinical research on metastatic castration-resistant prostate cancer (mCRPC) treatment, the potential enhanced efficacy of the combination of taxanes with AR-targeted agents, that is, enzalutamide and abiraterone, is currently being explored. Because enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug-drug interaction needs to be investigated. Experimental Design: Therefore, we performed a pharmacokinetic cross-over study in mCRPC patients who were scheduled for treatment with cabazitaxel Q3W (25 mg/m 2 ). Patients were studied for three consecutive cabazitaxel cycles. Enzalutamide (160 mg once daily) was administered concomitantly after the first cabazitaxel cycle, during 6 weeks. Primary endpoint was the difference in mean area under the curve (AUC) between the first (cabazitaxel monotherapy) and third cabazitaxel cycle, when enzalutamide was added. Results: A potential clinically relevant 22% (95% CI, 9%-34%; P = 0.005) reduction in cabazitaxel exposure was found with concomitant enzalutamide use. The geometric mean AUC 0-24h of cabazitaxel was 181 ng*h/mL (95% CI, 150-219 ng*h/mL) in cycle 3 and 234 ng*h/mL (95% CI, 209-261 ng*h/mL) in cycle 1. This combination did not result in excessive toxicity, whereas PSA response was promising. Conclusions: We found a significant decrease in cabazitaxel exposure when combined with enzalutamide. In an era of clinical trials on combination strategies for mCRPC, it is important to be aware of clinically relevant drug-drug interactions. Because recent study results support the use of a lower standard cabazitaxel dose of 20 mg/m 2 , the clinical relevance of this interaction may be substantial, because the addition of enzalutamide may result in subtherapeutic cabazitaxel exposure. Clin Cancer Res; 24(3); 541-6. ©2017 AACR .
(©2017 American Association for Cancer Research.)
Databáze: MEDLINE
Externí odkaz: