Darolutamide does not interfere with OATP-mediated uptake of docetaxel.

Autor: Buck SAJ; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Rotterdam, The Netherlands., Talebi Z; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA., Drabison T; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA., Jin Y; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA., Gibson AA; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA., Hu P; Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA., de Bruijn P; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Rotterdam, The Netherlands., de Ridder CMA; Department of Urology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Rotterdam, The Netherlands., Stuurman D; Department of Urology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Rotterdam, The Netherlands., Hu S; Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA., van Weerden WM; Department of Urology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Rotterdam, The Netherlands., Koolen SLW; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Rotterdam, The Netherlands., de Wit R; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Rotterdam, The Netherlands., Sparreboom A; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA., Mathijssen RHJ; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Rotterdam, The Netherlands., Eisenmann ED; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2024 Jul 15; Vol. 155 (2), pp. 314-323. Date of Electronic Publication: 2024 Mar 16.
DOI: 10.1002/ijc.34922
Abstrakt: The addition of darolutamide, an androgen receptor signalling inhibitor, to therapy with docetaxel has recently been approved as a strategy to treat metastatic prostate cancer. OATP1B3 is an SLC transporter that is highly expressed in prostate cancer and is responsible for the accumulation of substrates, including docetaxel, into tumours. Given that darolutamide inhibits OATP1B3 in vitro, we sought to characterise the impact of darolutamide on docetaxel pharmacokinetics. We investigated the influence of darolutamide on OATP1B3 transport using in vitro and in vivo models. We assessed the impact of darolutamide on the tumour accumulation of docetaxel in a patient-derived xenograft (PDX) model and on an OATP1B biomarker in patients. Darolutamide inhibited OATP1B3 in vitro at concentrations higher than the reported C max . Consistent with these findings, in vivo studies revealed that darolutamide does not influence the pharmacokinetics of Oatp1b substrates, including docetaxel. Docetaxel accumulation in PDX tumours was not decreased in the presence of darolutamide. Metastatic prostate cancer patients had similar levels of OATP1B biomarkers, regardless of treatment with darolutamide. Consistent with a low potential to inhibit OATP1B3-mediated transport in vitro, darolutamide does not significantly impede the transport of Oatp1b substrates in vivo or in patients. Our findings support combined treatment with docetaxel and darolutamide, as no OATP1B3 transporter based drug-drug interaction was identified.
(© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
Databáze: MEDLINE
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