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A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function

PURPOSE: Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function. METHODS: Cohorts A (normal renal function: creatinine clearance...

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Autores principales: Azaro, Analía, Rodón, Jordi, Machiels, Jean-Pascal, Rottey, Sylvie, Damian, Silvia, Baird, Richard, Garcia-Corbacho, Javier, Mathijssen, Ron H. J., Clot, Pierre-François, Wack, Claudine, Shen, Liji, de Jonge, Maja J. A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114328/
https://www.ncbi.nlm.nih.gov/pubmed/27796539
http://dx.doi.org/10.1007/s00280-016-3175-7
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author Azaro, Analía
Rodón, Jordi
Machiels, Jean-Pascal
Rottey, Sylvie
Damian, Silvia
Baird, Richard
Garcia-Corbacho, Javier
Mathijssen, Ron H. J.
Clot, Pierre-François
Wack, Claudine
Shen, Liji
de Jonge, Maja J. A.
author_facet Azaro, Analía
Rodón, Jordi
Machiels, Jean-Pascal
Rottey, Sylvie
Damian, Silvia
Baird, Richard
Garcia-Corbacho, Javier
Mathijssen, Ron H. J.
Clot, Pierre-François
Wack, Claudine
Shen, Liji
de Jonge, Maja J. A.
author_sort Azaro, Analía
collection PubMed
description PURPOSE: Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function. METHODS: Cohorts A (normal renal function: creatinine clearance [CrCL] >80 mL/min/1.73 m(2)), B (moderate renal impairment: CrCL 30 to <50 mL/min/1.73 m(2)) and C (severe impairment: CrCL <30 mL/min/1.73 m(2)) received cabazitaxel 25 mg/m(2) (A, B) or 20 mg/m(2) (C, could be escalated to 25 mg/m(2)), once every 3 weeks. Pharmacokinetic parameters and cabazitaxel unbound fraction (F (U)) were assessed using linear regression and mixed models. Geometric mean (GM) and GM ratios (GMRs) were determined using mean CrCL intervals (moderate and severe renal impairment: 40 and 15 mL/min/1.73 m(2)) versus a control (90 mL/min/1.73 m(2)). RESULTS: Overall, 25 patients received cabazitaxel (median cycles: 3 [range 1–20]; Cohort A: 5 [2–13]; Cohort B: 3 [1–15]; and Cohort C: 5 [1–20]), of which 24 were eligible for pharmacokinetic analysis (eight in each cohort). For moderate and severe renal impairment versus normal renal function, GMR estimates were: clearance normalized to body surface area (CL/BSA) 0.95 (90% CI 0.80–1.13) and 0.89 (0.61–1.32); area under the curve normalized to dose (AUC/dose) 1.06 (0.88–1.27) and 1.14 (0.76–1.71); and F (U) 0.99 (0.94–1.04) and 0.97 (0.87–1.09), respectively. Estimated slopes of linear regression of log parameters versus log CrCL (renal impairment) were: CL/BSA 0.06 (−0.15 to 0.28); AUC/dose −0.07 (−0.30 to 0.16); and F (U) 0.02 (−0.05 to 0.08). Cabazitaxel safety profile was consistent with previous reports. CONCLUSIONS: Renal impairment had no clinically meaningful effect on cabazitaxel pharmacokinetics.
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spelling pubmed-51143282016-12-02 A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function Azaro, Analía Rodón, Jordi Machiels, Jean-Pascal Rottey, Sylvie Damian, Silvia Baird, Richard Garcia-Corbacho, Javier Mathijssen, Ron H. J. Clot, Pierre-François Wack, Claudine Shen, Liji de Jonge, Maja J. A. Cancer Chemother Pharmacol Original Article PURPOSE: Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function. METHODS: Cohorts A (normal renal function: creatinine clearance [CrCL] >80 mL/min/1.73 m(2)), B (moderate renal impairment: CrCL 30 to <50 mL/min/1.73 m(2)) and C (severe impairment: CrCL <30 mL/min/1.73 m(2)) received cabazitaxel 25 mg/m(2) (A, B) or 20 mg/m(2) (C, could be escalated to 25 mg/m(2)), once every 3 weeks. Pharmacokinetic parameters and cabazitaxel unbound fraction (F (U)) were assessed using linear regression and mixed models. Geometric mean (GM) and GM ratios (GMRs) were determined using mean CrCL intervals (moderate and severe renal impairment: 40 and 15 mL/min/1.73 m(2)) versus a control (90 mL/min/1.73 m(2)). RESULTS: Overall, 25 patients received cabazitaxel (median cycles: 3 [range 1–20]; Cohort A: 5 [2–13]; Cohort B: 3 [1–15]; and Cohort C: 5 [1–20]), of which 24 were eligible for pharmacokinetic analysis (eight in each cohort). For moderate and severe renal impairment versus normal renal function, GMR estimates were: clearance normalized to body surface area (CL/BSA) 0.95 (90% CI 0.80–1.13) and 0.89 (0.61–1.32); area under the curve normalized to dose (AUC/dose) 1.06 (0.88–1.27) and 1.14 (0.76–1.71); and F (U) 0.99 (0.94–1.04) and 0.97 (0.87–1.09), respectively. Estimated slopes of linear regression of log parameters versus log CrCL (renal impairment) were: CL/BSA 0.06 (−0.15 to 0.28); AUC/dose −0.07 (−0.30 to 0.16); and F (U) 0.02 (−0.05 to 0.08). Cabazitaxel safety profile was consistent with previous reports. CONCLUSIONS: Renal impairment had no clinically meaningful effect on cabazitaxel pharmacokinetics. Springer Berlin Heidelberg 2016-10-27 2016 /pmc/articles/PMC5114328/ /pubmed/27796539 http://dx.doi.org/10.1007/s00280-016-3175-7 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Azaro, Analía
Rodón, Jordi
Machiels, Jean-Pascal
Rottey, Sylvie
Damian, Silvia
Baird, Richard
Garcia-Corbacho, Javier
Mathijssen, Ron H. J.
Clot, Pierre-François
Wack, Claudine
Shen, Liji
de Jonge, Maja J. A.
A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function
title A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function
title_full A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function
title_fullStr A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function
title_full_unstemmed A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function
title_short A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function
title_sort phase i pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114328/
https://www.ncbi.nlm.nih.gov/pubmed/27796539
http://dx.doi.org/10.1007/s00280-016-3175-7
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