Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment: a phase I dose-escalation study

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Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment: a phase I dose-escalation study

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Title: Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment: a phase I dose-escalation study
Author: Sarantopoulos, John; Mita, Alain C.; He, Aiwu; Wade, James L.; Hsueh, Chung-Tsen; Morris, John C.; Lockhart, A. Craig; Quinn, David I.; Hwang, Jimmy; Mier, James; Zhang, Wenping; Wack, Claudine; Yin, Jian; Clot, Pierre-François; Rixe, Olivier

Note: Order does not necessarily reflect citation order of authors.

Citation: Sarantopoulos, J., A. C. Mita, A. He, J. L. Wade, C. Hsueh, J. C. Morris, A. C. Lockhart, et al. 2017. “Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment: a phase I dose-escalation study.” Cancer Chemotherapy and Pharmacology 79 (2): 339-351. doi:10.1007/s00280-016-3210-8. http://dx.doi.org/10.1007/s00280-016-3210-8.
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Abstract: Purpose 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/m2 experienced DLTs; maximum tolerated dose (MTD) was 20 mg/m2. In C-3, two patients receiving 20 mg/m2 experienced 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.
Published Version: doi:10.1007/s00280-016-3210-8
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306058/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:31731619
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