UGT genotyping in belinostat dosing

Pharmacological Research : the Official Journal of the Italian Pharmacological Society
Andrew K L Goey, William D Figg

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 curre...Continue Reading

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Citations

May 18, 2016·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Dong DongBaojian Wu
Jan 17, 2019·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Rashmi R Shah
Feb 7, 2019·Physiological Reviews·Robyn MeechPeter I Mackenzie
Jun 14, 2018·Experimental and Therapeutic Medicine·Celia N Sanchez-DominguezRocio Ortiz-Lopez
Oct 10, 2018·Journal of Pharmaceutical Sciences·Aaron StewartDavid Vodak

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