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Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours
INTRODUCTION: ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. OBJECTIVES: This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokine...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937587/ https://www.ncbi.nlm.nih.gov/pubmed/33464545 http://dx.doi.org/10.1007/s40268-020-00336-x |
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author | Vermunt, Marit A. C. de Weger, Vincent A. Janssen, Julie M. Lopez-Yurda, Marta I. Keessen, Marianne Thijssen, Bas Rosing, Hilde Huitema, Alwin D. R. Beijnen, Jos H. Marchetti, Serena |
author_facet | Vermunt, Marit A. C. de Weger, Vincent A. Janssen, Julie M. Lopez-Yurda, Marta I. Keessen, Marianne Thijssen, Bas Rosing, Hilde Huitema, Alwin D. R. Beijnen, Jos H. Marchetti, Serena |
author_sort | Vermunt, Marit A. C. |
collection | PubMed |
description | INTRODUCTION: ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. OBJECTIVES: This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir. METHODS: Patients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03. RESULTS: In total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration–time curve (AUC)(0–48), AUC(0–inf) and maximum concentration (C(max)) were 1.11 (90% confidence interval [CI] 0.93–1.33), 1.19 (90% CI 1.00–1.41) and 1.07 (90% CI 0.81–1.42) in fed versus fasted conditions, respectively. For the ritonavir C(max), the GMR was 0.79 (90% CI 0.69–0.90), whereas the AUC(0–48) and AUC(0–inf) were bioequivalent. The most frequent treatment-related toxicities were grade ≤ 2 diarrhoea and fatigue. Hypokalaemia was the only observed treatment-related grade 3 toxicity. CONCLUSIONS: The docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir C(max). Since docetaxel exposure is the only clinically relevant parameter in our patient population, the overall conclusion is that combined ModraDoc006 and ritonavir treatment may be slightly affected by concomitant intake of a high-fat meal. In view of the small effect, it is most likely that the intake of a light meal will not affect the systemic exposure to docetaxel. CLINICALTRIALS.GOV IDENTIFIER: NCT03147378, date of registration: May 10 2017. |
format | Online Article Text |
id | pubmed-7937587 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-79375872021-03-21 Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours Vermunt, Marit A. C. de Weger, Vincent A. Janssen, Julie M. Lopez-Yurda, Marta I. Keessen, Marianne Thijssen, Bas Rosing, Hilde Huitema, Alwin D. R. Beijnen, Jos H. Marchetti, Serena Drugs R D Original Research Article INTRODUCTION: ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. OBJECTIVES: This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir. METHODS: Patients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03. RESULTS: In total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration–time curve (AUC)(0–48), AUC(0–inf) and maximum concentration (C(max)) were 1.11 (90% confidence interval [CI] 0.93–1.33), 1.19 (90% CI 1.00–1.41) and 1.07 (90% CI 0.81–1.42) in fed versus fasted conditions, respectively. For the ritonavir C(max), the GMR was 0.79 (90% CI 0.69–0.90), whereas the AUC(0–48) and AUC(0–inf) were bioequivalent. The most frequent treatment-related toxicities were grade ≤ 2 diarrhoea and fatigue. Hypokalaemia was the only observed treatment-related grade 3 toxicity. CONCLUSIONS: The docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir C(max). Since docetaxel exposure is the only clinically relevant parameter in our patient population, the overall conclusion is that combined ModraDoc006 and ritonavir treatment may be slightly affected by concomitant intake of a high-fat meal. In view of the small effect, it is most likely that the intake of a light meal will not affect the systemic exposure to docetaxel. CLINICALTRIALS.GOV IDENTIFIER: NCT03147378, date of registration: May 10 2017. Springer International Publishing 2021-01-19 2021-03 /pmc/articles/PMC7937587/ /pubmed/33464545 http://dx.doi.org/10.1007/s40268-020-00336-x Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Original Research Article Vermunt, Marit A. C. de Weger, Vincent A. Janssen, Julie M. Lopez-Yurda, Marta I. Keessen, Marianne Thijssen, Bas Rosing, Hilde Huitema, Alwin D. R. Beijnen, Jos H. Marchetti, Serena Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours |
title | Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours |
title_full | Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours |
title_fullStr | Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours |
title_full_unstemmed | Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours |
title_short | Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours |
title_sort | effect of food on the pharmacokinetics of the oral docetaxel tablet formulation modradoc006 combined with ritonavir (modradoc006/r) in patients with advanced solid tumours |
topic | Original Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937587/ https://www.ncbi.nlm.nih.gov/pubmed/33464545 http://dx.doi.org/10.1007/s40268-020-00336-x |
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