Oral docetaxel plus encequidar - a phase 1 clinical trial.

Autor: Wang D; Department of Anaesthesia, Waikato Hospital, Hamilton, New Zealand. David.wang@waikatodhb.health.nz., Hung N; Department of Pathology, University of Otago, Dunedin, New Zealand., Hung T; Zenith Technology Limited, Otago, New Zealand., Eden K; Dunedin Hospital, Dunedin, New Zealand., Chan WK; Athenex Limited, USA (Former association), Athens, USA., Kwan R; Athenex Limited, USA (Former association), Athens, USA., Qin A; PharmaEssentia Corporation, Taipei, Taiwan., Chang C; PharmaEssentia Corporation, Taipei, Taiwan., Duffull S; Certara, Wilmington, USA., Glue P; Department of Psychological Medicine, University of Otago, Dunedin, New Zealand., Jackson C; Department of Medicine, University of Otago, Dunedin, New Zealand.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2024 Sep; Vol. 94 (3), pp. 475-481. Date of Electronic Publication: 2024 May 30.
DOI: 10.1007/s00280-024-04674-4
Abstrakt: Purpose: To determine the bioavailability, safety, and tolerability of a single dose of oral docetaxel plus encequidar (oDox + E) and compare its pharmacokinetic exposure with current standard of care IV docetaxel.
Introduction: Docetaxel is a taxane widely used as an anti-neoplastic agent. Due to low oral bioavailability secondary to gut P-glycoprotein (P-gp) efflux, its current use is limited to intravenous administration. Oral docetaxel may provide a less resource intensive, more convenient, and tolerable alternative. Encequidar is a first in class, minimally absorbed, oral gut-specific P-gp inhibitor. We tested whether oDox + E can achieve comparable pharmacokinetic exposure to IV docetaxel.
Methods: A multicentre, phase I open-label, pharmacokinetic trial was undertaken to determine the bioavailability, safety, and tolerability of a single dose of oDox + E (at 75 mg/m2 + 15 mg, 150 mg/m2 + 15 mg, and 300 mg/m2 + 15 mg) in metastatic prostate cancer (mPC) patients compared to standard of care IV docetaxel as prescribed by their oncologists. The 15 mg of Encequidar at each dose level was given one hour prior to oral docetaxel.
Results: 11 patients were enrolled; 9 patients completed the study. Oral docetaxel exposure increased with dose, achieving the highest at 300 mg/m2 oDox + E (with AUC 0 - infinity of 1343.3 ± 443.0 ng.h/mL compared to the IV docetaxel AUC 0 - infinity of 2000 ± 325 ng.h/mL) and became non-linear at 300 mg/m 2 . The mean absolute bioavailability of oDox + E across all 3 dose levels was 16.14% (range: 8.19-25.09%). No patient deaths, dose limiting toxicity, treatment-related serious adverse event or grade 4 toxicity were observed. Maximal tolerated dose was not reached.
Conclusion: oDox + E has a safe and tolerable adverse event profile in patients with metastatic prostate cancer. The increase in oral bioavailability of oDox + E suggests a multi-dose oDox + E regimen could theoretically achieve exposures comparable with standard of care IV docetaxel. Further development to examine the optimal multiple dose regimen of oDox + E is warranted.
Trial Registration Number: U1111-1173-5473.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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