Back to Journals » Clinical Pharmacology: Advances and Applications » Volume 13

Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials

Authors Vermunt M, Marchetti S, Beijnen J

Received 19 November 2020

Accepted for publication 6 January 2021

Published 27 January 2021 Volume 2021:13 Pages 21—32


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Arthur Frankel

Marit Vermunt,1 Serena Marchetti,2 Jos Beijnen1,3,4

1Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam 1066, CX, the Netherlands; 2Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam 1066, CX, the Netherlands; 3Modra Pharmaceuticals B.V., Amsterdam 1083, HN, the Netherlands; 4Department of Pharmaceutical Sciences, Utrecht University, Utrecht 3584, CX, the Netherlands

Correspondence: Marit Vermunt
Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066, CX, the Netherlands
Tel +31 20 512 2127
Fax +31 20 512 4753

Introduction: Docetaxel is widely used as intravenous (IV) chemotherapy. Oral docetaxel is co-administered with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir to increase oral bioavailability. This research explores the relationship between the pharmacokinetics (PK) and toxicity of this novel oral chemotherapy.
Methods: The patients in two phase I trials were treated with different oral docetaxel formulations in combination with ritonavir in different dose levels, ranging from 20 to 80 mg docetaxel with 100 to 200 mg ritonavir a day. The patients were categorized based on the absence or occurrence of severe treatment-related toxicity (grade ≥ 3 or any grade leading to treatment alterations). The docetaxel area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax) were associated with toxicity.
Results: Thirty-four out of 138 patients experienced severe toxicity, most frequently observed as mucositis, fatigue, diarrhea, nausea and vomiting. The severe toxicity group had a significantly higher docetaxel AUC (2231 ± 1405 vs 1011 ± 830 ng/mL*h, p< 0.0001) and Cmax (218 ± 178 vs 119 ± 77 ng/mL, p< 0.0001) as compared to the patients without severe toxicity. When extrapolated from IV PK data, the patients without severe toxicity had a similar cumulative docetaxel AUC as with standard 3-weekly IV docetaxel, while the Cmax was up to 10-fold lower with oral docetaxel and ritonavir.
Conclusion: Severe toxicity was observed in 25% of the patients treated with oral docetaxel and ritonavir. This toxicity seems related to the PK, as the docetaxel AUC0-inf and Cmax were up to twofold higher in the severe toxicity group as compared to the non-severe toxicity group. Future randomized trials will provide a further evaluation of the toxicity and efficacy of the new weekly oral docetaxel and ritonavir regimen in comparison to standard IV docetaxel.

Keywords: oral docetaxel, ritonavir, pharmacokinetics, toxicity

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]