title: A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function.
abstract: OBJECTIVE
  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 (FU) 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 FU0.99 (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 FU0.02 (-0.05 to 0.08). Cabazitaxel safety profile was consistent with previous reports.
  
  
  CONCLUSIONS
  Renal impairment had no clinically meaningful effect on cabazitaxel pharmacokinetics.
authors: 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.
authors: Analía
authors: A
authors: Azaro
authors: Molecular Therapeutics Research Unit, Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors: Jordi
authors: J
authors: Rodón
authors: 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.
authors: Jean-Pascal
authors: JP
authors: Machiels
authors: Department of Medical Oncology, University Hospital of Ghent and Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
authors: Sylvie
authors: S
authors: Rottey
authors: Department of Medical Oncology, Fondazione IRCCS National Cancer Institute of Milan, Milan, Italy.
authors: Silvia
authors: S
authors: Damian
authors: Early Phase Clinical Trials Team, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Richard
authors: R
authors: Baird
authors: Early Phase Clinical Trials Team, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Javier
authors: J
authors: Garcia-Corbacho
authors: Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Ron H J
authors: RHJ
authors: Mathijssen
authors: Sanofi, Chilly-Mazarin, France.
authors: Pierre-François
authors: PF
authors: Clot
authors: Sanofi, Chilly-Mazarin, France.
authors: Claudine
authors: C
authors: Wack
authors: Sanofi, Bridgewater, NJ, USA.
authors: Liji
authors: L
authors: Shen
authors: Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Maja J A
authors: MJA
authors: de Jonge
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051437:Renal Insufficiency / Q000378:metabolism*; D043823:Taxoids / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; C552428:cabazitaxel
keywords: Advanced solid tumors; Cabazitaxel; Pharmacokinetics; Phase I; Renal impairment