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
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