Anthony B El-Khoueiry1, John Sarantopoulos2, Cindy L O'Bryant3, Kristen K Ciombor4, Huiping Xu5, Melissa O'Gorman6, Jayeta Chakrabarti7, Tiziana Usari8, Bassel F El-Rayes9. 1. Keck School of Medicine of University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA. elkhouei@med.usc.edu. 2. Institute for Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center San Antonio, San Antonio, TX, USA. 3. University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA. 4. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. 5. Pfizer Oncology, La Jolla, CA, USA. 6. Pfizer Oncology, Groton, CT, USA. 7. Pfizer Oncology, Tadworth, UK. 8. Pfizer Oncology, Milan, Italy. 9. Winship Cancer Institute, Emory University, Atlanta, GA, USA.
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.
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.
Authors: Elizabeth G Gibson; Olivia Campagne; Nicholas S Selvo; Amar Gajjar; Clinton F Stewart Journal: Cancer Chemother Pharmacol Date: 2021-09-29 Impact factor: 3.333