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Cancer Chemotherapy and Pharmacology

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Open Access 01-01-2019 | Short Communication

Lack of UGT polymorphism association with idasanutlin pharmacokinetics in solid tumor patients

Authors: W. Venus So, Tai-Hsien Ou Yang, Xing Yang, Jianguo Zhi

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2019

Abstract

Purpose

Idasanutlin is a selective small-molecule MDM2 antagonist. It activates the tumor suppressor TP53 and is in phase 3 clinical trial for acute myeloid leukemia. Nonclinical studies have shown that glucuronidation is the major metabolizing mechanism for idasanutlin and UGT1A3 is the major metabolizing enzyme. There are reported examples of UGT polymorphisms associated with drug metabolism or response. Thus, the aim of this analysis is to investigate if UGT polymorphism is associated with idasanutlin pharmacokinetics.

Method

Idasanutlin clearance was derived and normalized from two phase I studies. Its clearance level was compared between patients with different genotypes at 44 non-monomorphic UGT SNPs. Several single-locus and multi-locus association analysis, including haplotype association analysis and pairwise SNP interaction (epistasis) analyses were performed to investigate if there is any association between UGT genotypes and idasanutlin clearance.

Results and conclusion

A total of 69 patients who have both idasanutlin pharmacokinetic data and UGT genotyping data were analyzed for association. The major clearance enzyme for idasanutlin, UGT1A3, has no association with idasanutlin clearance. Further single-locus and multi-locus association analyses also suggest that no significant UGT polymorphism association with idasanutlin clearance can be detected with the current datasets. However, the possibility of association with rare allele(s) of UGT family genes cannot be excluded due to the limited sample size of the current phase I studies.

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Title: Lack of UGT polymorphism association with idasanutlin pharmacokinetics in solid tumor patients
Authors: W. Venus So
Tai-Hsien Ou Yang
Xing Yang
Jianguo Zhi
Publication date: 01-01-2019
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-018-3741-2

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