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Cancer Chemother Pharmacol. 2016 Dec;78(6):1185-1197. doi: 10.1007/s00280-016-3175-7. Epub 2016 Oct 27.

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

Author information

1
Molecular Therapeutics Research Unit, Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. aazaro@vhio.net.
2
Pharmacology Department, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. aazaro@vhio.net.
3
Molecular Therapeutics Research Unit, Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
4
Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels, Belgium.
5
Department of Medical Oncology, University Hospital of Ghent and Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
6
Department of Medical Oncology, Fondazione IRCCS National Cancer Institute of Milan, Milan, Italy.
7
Early Phase Clinical Trials Team, Department of Oncology, University of Cambridge, Cambridge, UK.
8
Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
9
Sanofi, Chilly-Mazarin, France.
10
Sanofi, Bridgewater, NJ, USA.

Abstract

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 m2), B (moderate renal impairment: CrCL 30 to <50 mL/min/1.73 m2) and C (severe impairment: CrCL <30 mL/min/1.73 m2) received cabazitaxel 25 mg/m2 (A, B) or 20 mg/m2 (C, could be escalated to 25 mg/m2), 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 m2) versus a control (90 mL/min/1.73 m2).

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.

KEYWORDS:

Advanced solid tumors; Cabazitaxel; Pharmacokinetics; Phase I; Renal impairment

PMID:
27796539
PMCID:
PMC5114328
DOI:
10.1007/s00280-016-3175-7
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Compliance with ethical standardsConflict of interestThis study was sponsored by Sanofi. Analía Azaro, Jordi Rodón, Silvia Damian, Javier Garcia-Corbacho and Maja de Jonge have no conflicts of interest to disclose. Jean-Pascal Machiels has been a member of advisory boards for Boehringer Ingelheim (without compensation) and MSD, and received research grants from Novartis, Bayer and Janssen. Sylvie Rottey has been a member of advisory boards and received research funding from Sanofi. Richard Baird and Ron Mathijssen have received research funding from Sanofi. Pierre-François Clot, Claudine Wack, and Liji Shen are employees of Sanofi. Liji Shen is a stock holder of Sanofi.Ethical approvalAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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