@article{eab2696399c042c3adf8bebfb30080b4,
title = "A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction",
abstract = "Aims: The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. Methods: We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction. Results: Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m2/day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. Conclusion: While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.",
keywords = "anticancer drugs, drug metabolism, drug safety, histone deacetylase inhibitor, liver disease",
author = "Naoko Takebe and Beumer, {Jan H.} and Shivaani Kummar and Kiesel, {Brian F.} and Afshin Dowlati and {O'Sullivan Coyne}, Geraldine and Richard Piekarz and Lawrence Rubinstein and Fogli, {Laura K.} and Ulka Vaishampayan and Sanjay Goel and O'Bryant, {Cindy L.} and El-Rayes, {Bassel F.} and Vincent Chung and Lenz, {Heinz Josef} and Richard Kim and Belani, {Chandra P.} and Tuscano, {Joseph M.} and William Schelman and Nancy Moore and Doroshow, {James H.} and Chen, {Alice P.}",
note = "Funding Information: This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract Number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This study was also supported by Topotarget A/S (Topotarget A/S has since merged with BioAlliance Pharma SA to form Onxeo) and by the following grants: U01‐CA099168, UM1‐CA186690 (NCI‐CTEP), R50 CA211241 (NCI). The PK study was performed using the UPMC Hillman Cancer Center Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30‐CA47904 and by Spectrum Pharmaceuticals. Funding Information: This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract Number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This study was also supported by Topotarget A/S (Topotarget A/S has since merged with BioAlliance Pharma SA to form Onxeo) and by the following grants: U01-CA099168, UM1-CA186690 (NCI-CTEP), R50 CA211241 (NCI). The PK study was performed using the UPMC Hillman Cancer Center Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30-CA47904 and by Spectrum Pharmaceuticals. Publisher Copyright: {\textcopyright} 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.",
year = "2019",
month = nov,
day = "1",
doi = "10.1111/bcp.14054",
language = "English (US)",
volume = "85",
pages = "2499--2511",
journal = "British Journal of Clinical Pharmacology",
issn = "0306-5251",
publisher = "Wiley-Blackwell",
number = "11",
}