Details

Autor(en) / Beteiligte

• Buck, Stefan A. J.
• Talebi, Zahra
• Drabison, Thomas
• Jin, Yan
• Gibson, Alice A.
• Hu, Peng
• Bruijn, Peter
• Ridder, Corrina M. A.
• Stuurman, Debra
• Hu, Shuiying
• Weerden, Wytske M.
• Koolen, Stijn L. W.
• Wit, Ronald
• Sparreboom, Alex
• Mathijssen, Ron H. J.
• Eisenmann, Eric D.

Titel

Darolutamide does not interfere with OATP‐mediated uptake of docetaxel

Ist Teil von

• International journal of cancer, 2024-07, Vol.155 (2), p.314-323

Ort / Verlag

Hoboken, USA: John Wiley & Sons, Inc

Erscheinungsjahr

2024

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 Cmax. 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. What's new? The combination of docetaxel and the androgen receptor inhibitor darolutamide can improve sur‐vival in metastatic hormone‐sensitive prostate cancer patients. To enter tumor cells, docetaxel us‐es the drug transporter OATP1B3, which may be inhibited by darolutamide. Here, using in vitro and in vivo models and clinical samples, the authors investigated the impact of darolutamide on docetaxel pharmacokinetics. Darolutamide inhibited OATP1B3 but only above maximum serum concentrations. The drug had no impact on docetaxel accumulation in patient‐derived xenograft tumors or OATP1B biomarkers in patient samples. An absence of drug trans‐porter‐related pharmacokinetic interactions supports the combined use of docetaxel and darolu‐tamide.