Belinostat response

Belinostat is a histone deacetylase (HDAC) inhibitor, approved for the treatment of relapsed or refractory peripheral T-cell lymphomas (PTCLs). Belinostat targets 3 classes of HDACs (I, II and IV), resulting in higher levels of acetylation of both histone and non-histone proteins, thus reversing the changes in protein acetylation that are frequently disrupted during oncogenesis. Belinostat is administered as an infusion at a rate of 1000 mg/m2 for 30 minutes on days 1–5 of a 21-day cycle. Belinostat has a relatively short half-life and is primarily metabolized by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1)-mediated glucuronidation, with minor contributions from other UGT and cytochrome P450 (CYP) enzymes. Genetic variation at the UGT1A1 locus can result in decreased enzyme activity and thus increased exposure to belinostat. The US Food and Drug Administration (FDA)-approved drug label recommends a 25% decrease in dose for individuals who are known to be homozygous for the UGT1A1*28 reduced function allele. Additional indications for dose reduction include grade 3 or 4 adverse reactions or significant decrease in neutrophil or platelet counts following belinostat administration. Some studies have suggested that other variant alleles may also lead to increased belinostat exposure, such as UGT1A1*60; however, no specific recommendations for dose reduction have been made for these alleles by either the FDA or other professional pharmacogenetic consortia. Belinostat should not be administered with other medications that can inhibit UGT1A1 function, such as nilotinib, ketoconazole, or ripretinib. [from Medical Genetics Summaries]