UGT genotyping in belinostat dosing

Certain genetic polymorphisms of UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) can reduce gene expression (∗28,∗60,∗93) or activity (∗6), thereby altering the pharmacokinetics, pharmacodynamics, and the risk of toxicities of UGT1A1 substrates, of which irinotecan is a widely-described example. This review presents an overview of the clinical effects of UGT1A1 polymorphisms on the pharmacology of UGT1A1 substrates, with a special focus on the novel histone deacetylase inhibitor belinostat. Belinostat, approved for the treatment of peripheral T-cell lymphoma, is primarily glucuronidated by UGT1A1. Recent preclinical and clinical data showed that UGT1A1∗28 was associated with reduced glucuronidation in human liver microsomes, while in a retrospective analysis of a Phase I trial with patients receiving belinostat UGT1A1∗60 was predominantly associated with increased belinostat plasma concentrations. Furthermore, both UGT1A1∗28 and∗60 variants were associated with increased incidence of thrombocytopenia and neutropenia. Using population pharmacokinetic analysis a 33% dose reduction has been proposed for patients carrying UGT1A1 variant alleles. Clinical effects of this genotype-based dosing recommendation is currently prospectively being investigated. Overall, the data suggest that UGT1A1 genotyping is useful for improving belinostat therapy. Published by Elsevier Ltd.