Pharmacokinetics and safety of vismodegib in patients with advanced solid malignancies and hepatic impairment

被引:24
作者
Abou-Alfa, Ghassan K. [1 ,2 ]
Lewis, Lionel D. [3 ,4 ]
LoRusso, Patricia [5 ]
Maitland, Michael [6 ]
Chandra, Priya [7 ]
Cheeti, Sravanthi [7 ]
Colburn, Dawn [7 ]
Williams, Sarah [8 ]
Simmons, Brian [7 ]
Graham, Richard A. [7 ,9 ]
机构
[1] Mem Sloan Kettering Canc Ctr, 300 East 66th St, New York, NY 10065 USA
[2] Weill Cornell Med Coll, New York, NY 10065 USA
[3] Norris Cotton Canc Ctr, Hanover, NH USA
[4] Geisel Sch Med Dartmouth, Hanover, NH USA
[5] Barbara Ann Karmanos Canc Inst, Detroit, MI USA
[6] Univ Chicago, Med Ctr, Chicago, IL 60637 USA
[7] Genentech Inc, San Francisco, CA 94080 USA
[8] Roche Prod Ltd, Welwyn Garden City, Herts, England
[9] Theravance Biopharma, San Francisco, CA USA
关键词
Vismodegib; Hepatic; Impairment; Safety; Pharmacokinetics; MASS-SPECTROMETRY; PHASE EXTRACTION; HEDGEHOG PATHWAY; HUMAN PLASMA; INHIBITOR; GDC-0449; CANCER;
D O I
10.1007/s00280-017-3315-8
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Vismodegib is a Hedgehog pathway inhibitor approved for the treatment of advanced basal cell carcinoma. Currently, the pharmacokinetics (PK) and safety of vismodegib in patients with hepatic dysfunction are unknown and are the objective of this study. Patients with advanced solid malignancies and hepatic impairment were enrolled into one of four cohorts: normal [bilirubin (bili) < upper limit of normal (ULN)], mild (ULN < bili ae<currency> 1.5 x ULN), moderate (1.5 x ULN < bili ae<currency> 3xULN), and severe (3 x ULN < bili < 10 x ULN) dysfunction. Patients received oral vismodegib 150 mg daily. Plasma PK samples on days 1, 3, 5, and 8 were collected. Vismodegib therapy was continued until disease progression, intolerable toxicity, or withdrawal of consent. Thirty-one patients were accrued: nine normal, eight mild, eight moderate, and six severe. Four patients experienced dose-limiting toxicity of hyperbilirubinemia on study: one in the moderate cohort and three in the severe cohort. Six patients died within 30 days after the last dose of vismodegib. All deaths were attributed to disease progression. Observed maximal and average steady-state concentrations and AUC of vismodegib at steady state (day 8) were similar across cohorts. Average AAG concentrations in patients with hepatic impairment were comparable to those of patients with normal hepatic function. Hepatic impairment does not appear to impact vismodegib PK, and therefore, dose adjustment is not necessary in this special population. The study was influenced by the high number of patients with hepatocellular carcinoma with advanced cirrhosis; rendering it difficult to draw any causal relationships between vismodegib exposure and the serious adverse events.
引用
收藏
页码:29 / 36
页数:8
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