TY - JOUR
T1 - UGT genotyping in belinostat dosing
AU - Goey, Andrew K.L.
AU - Figg, William D.
N1 - Funding Information:
We thank Dr. Cindy H. Chau for critically reviewing the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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.
AB - 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.
KW - Belinostat
KW - Pharmacodynamics
KW - Pharmacogenomics
KW - Pharmacokinetics
KW - Polymorphisms
KW - UGT1A1
UR - http://www.scopus.com/inward/record.url?scp=84955513271&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2016.01.002
DO - 10.1016/j.phrs.2016.01.002
M3 - Review article
C2 - 26773202
AN - SCOPUS:84955513271
SN - 1043-6618
VL - 105
SP - 22
EP - 27
JO - Pharmacological Research
JF - Pharmacological Research
ER -