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

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 Pharmaceutica...

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Autores principales:	Vermunt M, Marchetti S, Beijnen J
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	oral docetaxel ritonavir pharmacokinetics toxicity Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/091def07b27d48a1b852653d790f61e6
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spelling	oai:doaj.org-article:091def07b27d48a1b852653d790f61e62021-12-02T14:08:53ZPharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials1179-1438https://doaj.org/article/091def07b27d48a1b852653d790f61e62021-01-01T00:00:00Zhttps://www.dovepress.com/pharmacokinetics-and-toxicities-of-oral-docetaxel-formulations-co-admi-peer-reviewed-article-CPAAhttps://doaj.org/toc/1179-1438Marit 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 NetherlandsCorrespondence: Marit VermuntDepartment of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066, CX, the NetherlandsTel +31 20 512 2127Fax +31 20 512 4753Email m.vermunt@nki.nlIntroduction: 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, toxicityVermunt MMarchetti SBeijnen JDove Medical Pressarticleoral docetaxelritonavirpharmacokineticstoxicityTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol Volume 13, Pp 21-32 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	oral docetaxel ritonavir pharmacokinetics toxicity Therapeutics. Pharmacology RM1-950
spellingShingle	oral docetaxel ritonavir pharmacokinetics toxicity Therapeutics. Pharmacology RM1-950 Vermunt M Marchetti S Beijnen J Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials
description	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 NetherlandsCorrespondence: Marit VermuntDepartment of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066, CX, the NetherlandsTel +31 20 512 2127Fax +31 20 512 4753Email m.vermunt@nki.nlIntroduction: 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
format	article
author	Vermunt M Marchetti S Beijnen J
author_facet	Vermunt M Marchetti S Beijnen J
author_sort	Vermunt M
title	Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials
title_short	Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials
title_full	Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials
title_fullStr	Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials
title_full_unstemmed	Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials
title_sort	pharmacokinetics and toxicities of oral docetaxel formulations co-administered with ritonavir in phase i trials
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/091def07b27d48a1b852653d790f61e6
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Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials

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