title: Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment: a phase I dose-escalation study.
abstract: OBJECTIVE
  Cabazitaxel has not been studied in patients with hepatic impairment (HI). This phase I study assessed cabazitaxel safety and pharmacokinetics in patients with HI.
  
  
  METHODS
  Patients with advanced, non-hematologic cancer, and normal hepatic function (Cohort 1: C-1), or mild (C-2), moderate (C-3), severe (C-4) HI received cabazitaxel starting doses of 25, 20, 10, and 10 mg/m2, respectively. Doses were escalated in patients with HI based on Cycle 1 dose-limiting toxicities (DLTs). Adverse events and the cabazitaxel pharmacokinetic profile were assessed.
  
  
  RESULTS
  In C-2, three patients receiving cabazitaxel 25 mg/m2experienced DLTs; maximum tolerated dose (MTD) was 20 mg/m2. In C-3, two patients receiving 20 mg/m2experienced DLTs; MTD was 15 mg/m2. C-4 was discontinued early due to DLTs. The most frequent cabazitaxel-related, grade 3-4 toxicity was neutropenia (42%). Cabazitaxel clearance normalized to body surface area (CL/BSA) was lower in C-1 (geometric mean [GM] 13.4 L/h/m2) than expected (26.4 L/h/m2), but similar in C-2 (23.5 L/h/m2) and C-3 (27.9 L/h/m2). CL/BSA in C-4 was 18.1 L/h/m2. Compared with C-2, CL/BSA increased 19% in C-3 (GM ratio 1.19; 90% CI 0.74-1.91), but decreased 23% in C-4 (0.77; 0.39-1.53). Cabazitaxel free fraction was unaltered. No significant correlation was found between grade 3-4 toxicities and pharmacokinetic parameters.
  
  
  CONCLUSIONS
  Mild-moderate HI did not cause substantial decline in cabazitaxel clearance. Cabazitaxel dose reductions in patients with mild-moderate HI, and a contraindication in patients with severe HI, are justified based on safety data.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.affiliation: Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.affiliation: Department of Medicine and Oncology and Innovation Center for Biomedical Informatics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Aiwu
authors.initials: A
authors.lastname: He
authors.affiliation: Division of Medical Oncology/Hematology, Cancer Care Center of Decatur, Decatur, IL, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Wade
authors.affiliation: Division of Medical Oncology/Hematology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Chung-Tsen
authors.initials: CT
authors.lastname: Hsueh
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Cincinnati Cancer Institute, Cincinnati, OH, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: A Craig
authors.initials: AC
authors.lastname: Lockhart
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.affiliation: Department of Medicine and Oncology and Innovation Center for Biomedical Informatics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Medicine, Dana-Farber/Harvard Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Mier
authors.affiliation: Sanofi, Bridgewater, NJ, USA.
authors.forename: Wenping
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Sanofi, Chilly-Mazarin, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Wack
authors.affiliation: Sanofi, Bridgewater, NJ, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yin
authors.affiliation: Sanofi, Chilly-Mazarin, France.
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Clot
authors.affiliation: Division of Hematology/Oncology, Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA. ORixe@salud.unm.edu.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rixe
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D005260:Female; D006801:Humans; D017093:Liver Failure / Q000378:metabolism*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D043823:Taxoids / Q000009:adverse effects* / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; C552428:cabazitaxel
keywords: Cabazitaxel; Hepatic impairment; Maximum tolerated dose; Pharmacokinetics; Phase I