Phase 1 summary of plasma concentration–QTc analysis for idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors and AML

Phase 1 summary of plasma concentration–QTc analysis for idasanutlin, an MDM2 antagonist, in... Purpose Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non- genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval. Method Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from base- line (Δ) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed effect model. Categorical analysis was also performed. Results A total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma concentration. There was no apparent increase of QTcF or ΔQTcF in a wide idasanutlin plasma concentration range, even at concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical analysis did not detect a potential signal of QT prolongation. Conclusion The concentration–QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted concentration range currently in consideration for http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Chemotherapy and Pharmacology Springer Journals

Phase 1 summary of plasma concentration–QTc analysis for idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors and AML

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Publisher
Springer Journals
Copyright
Copyright © 2018 by Springer-Verlag GmbH Germany, part of Springer Nature
Subject
Medicine & Public Health; Oncology; Pharmacology/Toxicology; Cancer Research
ISSN
0344-5704
eISSN
1432-0843
D.O.I.
10.1007/s00280-018-3534-7
Publisher site
See Article on Publisher Site

Abstract

Purpose Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non- genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval. Method Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from base- line (Δ) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed effect model. Categorical analysis was also performed. Results A total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma concentration. There was no apparent increase of QTcF or ΔQTcF in a wide idasanutlin plasma concentration range, even at concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical analysis did not detect a potential signal of QT prolongation. Conclusion The concentration–QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted concentration range currently in consideration for

Journal

Cancer Chemotherapy and PharmacologySpringer Journals

Published: Feb 1, 2018

References

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