title: UGT genotyping in belinostat dosing.
abstract: 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.
authors.affiliation: Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: andrew.goey@nih.gov.
authors.forename: Andrew K L
authors.initials: AK
authors.lastname: Goey
authors.affiliation: Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: figgw@helix.nih.gov.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D060005:Genotyping Techniques; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D016411:Lymphoma, T-Cell, Peripheral / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D013449:Sulfonamides / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D000099148:UGT1A1 Enzyme
chemical_list: D000970:Antineoplastic Agents; D014453:Glucuronosyltransferase; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D000099148:UGT1A1 Enzyme; C487081:belinostat
keywords: Belinostat; Pharmacodynamics; Pharmacogenomics; Pharmacokinetics; Polymorphisms; UGT1A1