Evaluation of hepatic impairment on pharmacokinetics and safety of crizotinib in patients with advanced cancer

Cancer Chemotherapy and Pharmacology
Anthony B El-KhoueiryBassel F El-Rayes

Abstract

This phase 1 study evaluated the effect of hepatic impairment on pharmacokinetics and safety of crizotinib in patients with advanced cancer. Patients were dosed according to hepatic function classified by modified National Cancer Institute Organ Dysfunction Working Group criteria and group assignment [normal (A1 and A2), mild (B), moderate (C1 and C2), or severe (D)]. Primary pharmacokinetic endpoints included area under the concentration-time curve as daily exposure (AUCdaily) and maximum plasma concentration (Cmax) at steady state. Safety endpoints included types, incidence, seriousness, and relationship to crizotinib of adverse events. The AUCdaily and Cmax in patients with normal liver function were 7107 ng h/mL and 375.1 ng/mL (A1) and 5422 ng h/mL and 283.9 ng/mL (A2), respectively. The AUCdaily and Cmax ratios of adjusted geometric means for Groups B, C2, and D versus Group A1 were 91.12 and 91.20, 114.08 and 108.87, and 64.47 and 72.63, respectively. Any grade treatment-related adverse events (TRAEs) occurred in 75% of patients; grade 3/4 TRAEs occurred in 25%, including fatigue (6%), hyponatremia (5%), and hyperbilirubinemia (3%). No adjustment to the approved 250 mg twice daily (BID) dose of crizotinib is recommended ...Continue Reading

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Citations

Jan 17, 2019·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Alberto PucciniFrancesca Battaglin
May 21, 2020·Drug Design, Development and Therapy·Dehua ZhaoJisheng Wang
Jun 20, 2018·Clinical Pharmacokinetics·Takeshi HirotaIchiro Ieiri
Apr 29, 2021·Cancer Chemotherapy and Pharmacology·Nikolay GrechkoJim Xiao
Sep 24, 2021·Transplant International : Official Journal of the European Society for Organ Transplantation·Umberto MaggiorePaolo Cravedi
Nov 27, 2021·Clinical Pharmacology in Drug Development·Huiping XuAkintunde Bello

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