Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 1, pp 53–64

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

  • Anthony El-Khoueiry
  • James A. Posey
  • Juan Ramón Castillo Ferrando
  • Smitha S. Krishnamurthi
  • Shariq Syed
  • Georgia Kollia
  • Ian Walters
  • Bruce S. Fischer
  • Eric Masson
Original Article

DOI: 10.1007/s00280-013-2168-z

Cite this article as:
El-Khoueiry, A., Posey, J.A., Castillo Ferrando, J.R. et al. Cancer Chemother Pharmacol (2013) 72: 53. doi:10.1007/s00280-013-2168-z

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.

Keywords

BrivanibHepatocellular carcinomaLiver impairmentPharmacokinetics

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Anthony El-Khoueiry
    • 1
  • James A. Posey
    • 2
  • Juan Ramón Castillo Ferrando
    • 3
  • Smitha S. Krishnamurthi
    • 4
  • Shariq Syed
    • 5
  • Georgia Kollia
    • 6
  • Ian Walters
    • 6
  • Bruce S. Fischer
    • 6
  • Eric Masson
    • 6
  1. 1. USC Norris Comprehensive Cancer CenterLos AngelesUSA
  2. 2.University of Alabama at BirminghamBirminghamUSA
  3. 3.Clinical Assay Unit Phase I–IIVirgen del Rocío University Hospital, Seville UniversitySevilleSpain
  4. 4.Case Western Reserve University/University Hospitals Case Medical CenterClevelandUSA
  5. 5.PiscatawayUSA
  6. 6.Bristol-Myers SquibbPrincetonUSA