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Related Experiment Video

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Comprehensive Analysis of Drug Response using the FLICK Assay
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UGT genotyping in belinostat dosing.

Andrew K L Goey1, William D Figg1

  • 1Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Pharmacological Research
|January 17, 2016
PubMed
Summary

Genetic variations in UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) impact drug metabolism. UGT1A1 genotyping can personalize belinostat therapy, reducing toxicity and improving patient outcomes.

Keywords:
BelinostatPharmacodynamicsPharmacogenomicsPharmacokineticsPolymorphismsUGT1A1

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Area of Science:

  • Pharmacogenomics
  • Drug Metabolism
  • Oncology

Background:

  • Genetic polymorphisms in UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) affect the metabolism of its substrates.
  • UGT1A1 plays a crucial role in the glucuronidation of various drugs, including chemotherapy agents like irinotecan and the histone deacetylase inhibitor belinostat.

Purpose of the Study:

  • To review the clinical impact of UGT1A1 genetic variations on the pharmacology of UGT1A1 substrates.
  • To focus on the specific effects of UGT1A1 polymorphisms on belinostat therapy in patients with peripheral T-cell lymphoma.

Main Methods:

  • Review of preclinical and clinical data on UGT1A1 polymorphisms and belinostat.
  • Retrospective analysis of a Phase I trial involving belinostat.
  • Population pharmacokinetic analysis to determine optimal dosing strategies.

Main Results:

  • UGT1A1*28 polymorphism is linked to reduced belinostat glucuronidation.
  • UGT1A1*60 variant is associated with increased belinostat plasma concentrations.
  • Both UGT1A1*28 and *60 variants correlate with a higher incidence of thrombocytopenia and neutropenia.

Conclusions:

  • UGT1A1 genotyping can identify patients at higher risk for belinostat-related toxicities.
  • A 33% dose reduction is proposed for patients with UGT1A1 variant alleles.
  • UGT1A1 genotyping is a valuable tool for optimizing belinostat treatment efficacy and safety.