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

Abstract

Purpose: This phase 1 study evaluated the effect of hepatic impairment on pharmacokinetics and safety of crizotinib in patients with advanced cancer.

Methods: 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.

Results: 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%).

Conclusions: No adjustment to the approved 250 mg twice daily (BID) dose of crizotinib is recommended for patients with mild hepatic impairment. The recommended dose is 200 mg BID for patients with moderate hepatic impairment, and the dose should not exceed 250 mg daily for patients with severe hepatic impairment. Adverse events appeared consistent among the hepatic impairment groups.

Clinical trial registration no: NCT01576406.

Keywords: Advanced cancer; Crizotinib; Hepatic impairment; Pharmacokinetics.

Conflict of interest statement

Conflict of interest ABE-K has served as a consultant, advisor, or speaker for AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, CytomX, Merrimack Pharmaceutical, and Roche-Genentech. CLO has served as a consultant, advisor, or speaker for Amgen, Bristol-Myers Squibb, and Heron Therapeutics and has received research funding from AstraZeneca and Bayer. KKC has received research funding from Bayer, Boston Biomedical, Incyte, MedImmune, Merck, Novartis, Pfizer, and Sanofi. HX is an employee of and owns stock in Pfizer and holds a patent or receives royalties from GTx Inc. MO is an employee of Pfizer. JC and TU are employees of and own stock in Pfizer. BFE-R has served as a consultant or advisor for BTG International, Lexicon, and Merrimack Pharmaceutical, and has received research funding from AVEO Pharmaceuticals, Boston Biomedical, Bristol-Myers Squibb, Cleave Biosciences, Inc., Genentech, Hoosier Cancer Research Network, Inc., Merck, Novartis, and TAIHO Oncology.

Figures

Fig. 1

Between-group comparisons of crizotinib exposure parameters at steady state (cycle 2, day 1). a Mean crizotinib concentration versus time curves for Groups A1 through D. b Individual values and geometric mean AUCdaily and Cmax values for Groups A1 through D. Median is indicated by the line in the boxes. Box plot, 25%/75% quartiles with whiskers to the last point within 1.5 times the interquartile range. AUCdaily area under the plasma concentration–time curve as daily exposure, BID twice daily, Cmax maximum observed plasma concentration, QD once daily