P-0022 - Pharmacokinetics of sunitinib in patients with liver cirrhosis and hepatocellular carcinoma

Date 28 June 2014
Event World GI 2014
Session Poster Session
Topics Anti-Cancer Agents & Biologic Therapy
Pharmacology
Hepatobiliary Cancers
Presenter Marco Biolato
Citation Annals of Oncology (2014) 25 (suppl_2): ii14-ii104. 10.1093/annonc/mdu165
Authors M. Biolato1, M. Basso2, E. Strocchi3, A. Amoruso4, L. Miele5, M. Campitiello2, M. Pompili5, A. Grieco5, C. Barone6
  • 1Department Of Internal Medicine, Catholic University of Sacred Heart, Rome/IT
  • 2Medical Oncology, Catholic University of Sacred Heart, Rome/IT
  • 3Department of Industrial Chemistry “Toso Montanari”, University of Bologna, Bologna/IT
  • 4Medical Oncology, Catholic University of Sacred Heart, , Italy, Rome/IT
  • 5Department of Internal Medicine, Catholic University of Sacred Heart, Rome/IT
  • 6UOC di Oncologia Medica, Università Cattolica del S. Cuore, Rome/IT

Abstract

Introduction

Sunitinib is a multitargeted tyrosine kinase inhibitor currently employed in renal-cell carcinoma, gastrointestinal stromal tumour, pancreatic neuroendocrine tumors. Sunitinib is metabolized by hepatic CYP3A4 and biliary excreted, but pharmacokinetic in patients with liver cirrhosis is poorly known. Aim of the study is to characterize the pharmacokinetics of sunitinib in cirrhotic patients with hepatocellular carcinoma (HCC).

Methods

15 cirrhotic patients (mean age 68.2 years, 13 male, 11 Child-Pugh A, 4 Child-Pugh B) enrolled in a phase II study on HCC (Dig Liver Dis 2013;45:692-8) received sunitinib 50 mg daily on a 4-week-on-2-week-off schedule. Blood samples were collected at 0,1,2,4,8,12,18, and 24 hours after the first oral dose and at 3rd, 4th and 28th days later. Drug plasma concentrations were measured by a validated HPLC method. Non-compartmental Statistical Moment Theory was used for pharmacokinetic parameters.

Results

Sunitinib maximum concentration (Cmax) of 82.4 + 81.8 ng/mL was observed after 12.9 + 8.1 hours (Tmax). Area Under the Curve (AUC0-24) was equal to 1128.5 + 985.6 ng*h/mL and Mean Residence Time (MRT) equal to 59.7 + 43.4 hours, markedly higher than values reported for patients with healthy liver (J Clin Oncol 2006;24:25-35). 9/15 patients discontinued sunitinib for adverse events, but AUC0-24 or MRT were not statistically different compared with patients that stopped drug for progression. Among liver function tests, pre-treatment alkaline phosphatase was linearly related to AUC0-24 (r2 = 0.33) and inversely related to MRT (r2 = 0.26).

Conclusion

Pharmacokinetics of sunitinib in patients with cirrhosis differ markedly from data published for patients with healthy liver, so it is plausible to assume an individualized dose in cirrhotic patients.