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

Autor: Azaro A; Molecular Therapeutics Research Unit, Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. aazaro@vhio.net.; Pharmacology Department, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. aazaro@vhio.net., Rodón J; Molecular Therapeutics Research Unit, Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain., Machiels JP; 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., Rottey S; Department of Medical Oncology, University Hospital of Ghent and Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium., Damian S; Department of Medical Oncology, Fondazione IRCCS National Cancer Institute of Milan, Milan, Italy., Baird R; Early Phase Clinical Trials Team, Department of Oncology, University of Cambridge, Cambridge, UK., Garcia-Corbacho J; Early Phase Clinical Trials Team, Department of Oncology, University of Cambridge, Cambridge, UK., Mathijssen RHJ; Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands., Clot PF; Sanofi, Chilly-Mazarin, France., Wack C; Sanofi, Chilly-Mazarin, France., Shen L; Sanofi, Bridgewater, NJ, USA., de Jonge MJA; Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2016 Dec; Vol. 78 (6), pp. 1185-1197. Date of Electronic Publication: 2016 Oct 27.
DOI: 10.1007/s00280-016-3175-7
Abstrakt: 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.
Competing Interests: 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.
Databáze: MEDLINE
Externí odkaz: