NDLI: UGT genotyping in belinostat dosing.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Goey, Andrew K. L. Figg, William D.
Description	Author Affiliation: Goey AK ( Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: andrew.goey@nih.gov.); Figg WD ( Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: figgw@helix.nih.gov.)
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 UGT1A128 was associated with reduced glucuronidation in human liver microsomes, while in a retrospective analysis of a Phase I trial with patients receiving belinostat UGT1A160 was predominantly associated with increased belinostat plasma concentrations. Furthermore, both UGT1A128 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.
File Format	HTM / HTML
ISSN	10436618
Volume Number	105
e-ISSN	10961186
Journal	Pharmacological Research
Language	English
Publisher	Elsevier
Publisher Date	2016-03-01
Publisher Place	Netherlands
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Discipline Pharmacology Antineoplastic Agents Therapeutic Use Glucuronosyltransferase Genetics Histone Deacetylase Inhibitors Hydroxamic Acids Polymorphism, Genetic Sulfonamides Animals Administration & Dosage Pharmacokinetics Pharmacology Genotyping Techniques Metabolism Humans Lymphoma, T-cell, Peripheral Drug Therapy Pharmacogenetics Journal Article Research Support, N.i.h., Intramural Review
Content Type	Text
Resource Type	Article
Subject	Pharmacology

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