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  • Title: The effects of liver impairment on the pharmacokinetics of brivanib, a dual inhibitor of fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases.
    Author: El-Khoueiry A, Posey JA, Castillo Ferrando JR, Krishnamurthi SS, Syed S, Kollia G, Walters I, Fischer BS, Masson E.
    Journal: Cancer Chemother Pharmacol; 2013 Jul; 72(1):53-64. PubMed ID: 23719718.
    Abstract:
    PURPOSE: Hepatic impairment may impede tyrosine kinase inhibitor metabolism. This phase I study compared the pharmacokinetics of brivanib in patients with hepatocellular carcinoma (HCC) and varying levels of hepatic impairment with those with non-HCC malignancies and normal liver function. METHODS: Patients were assigned to the following groups: Groups A, B, and C (HCC plus mild, moderate, or severe hepatic impairment, respectively) and Group D (non-HCC malignancy and normal hepatic function). Brivanib alaninate (brivanib prodrug) doses were 400 mg in Groups A, B, and D and 200 mg in Group C. Brivanib exposure was determined on day 1 (single dose) and day 28 (multiple doses). RESULTS: Twenty-four patients participated in the study. After a single brivanib alaninate dose, brivanib exposure was comparable between Groups A, B, and D. Area under the concentration-time curve was 50 % higher in Group C versus Group D. There were not enough data to draw conclusions on multiple doses. Safety profile in Groups A, B, and D was consistent with previous brivanib monotherapy experience. Tolerability could not be assessed in Group C because of dose interruptions and discontinuations, generally due to the disease natural history. CONCLUSIONS: Brivanib exposure was similar in patients with HCC and mild or moderate hepatic impairment (Child-Pugh [CP] A or B status) and those with non-HCC malignancies and normal hepatic function, suggesting dose adjustment is unnecessary with CP A or B status. Experience with HCC and severe hepatic impairment (CP C status) is insufficient to recommend brivanib use in this population.
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