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Publication Detail

Title: Identification of Candidate Risk Factor Genes for Human Idelalisib Toxicity Using a Collaborative Cross Approach.

Authors: Mosedale, Merrie; Cai, Yanwei; Eaddy, John Scott; Corty, Robert W; Nautiyal, Manisha; Watkins, Paul B; Valdar, William

Published In Toxicol Sci, (2019 12 01)

Abstract: Idelalisib is a phosphatidylinositol 3-kinase inhibitor highly selective for the delta isoform that has shown good efficacy in treating chronic lymphocytic leukemia and follicular lymphoma. In clinical trials, however, idelalisib was associated with rare, but potentially serious liver and lung toxicities. In this study, we used the Collaborative Cross (CC) mouse population to identify genetic factors associated with the drug response that may inform risk management strategies for idelalisib in humans. Eight male mice (4 matched pairs) from 50 CC lines were treated once daily for 14 days by oral gavage with either vehicle or idelalisib at a dose selected to achieve clinically relevant peak plasma concentrations (150 mg/kg/day). The drug was well tolerated across all CC lines, and there were no observations of overt liver injury. Differences across CC lines were seen in drug concentration in plasma samples collected at the approximate Tmax on study Days 1, 7, and 14. There were also small but statistically significant treatment-induced alterations in plasma total bile acids and microRNA-122, and these may indicate early hepatocellular stress required for immune-mediated hepatotoxicity in humans. Idelalisib treatment further induced significant elevations in the total cell count of terminal bronchoalveolar lavage fluid, which may be analogous to pneumonitis observed in the clinic. Genetic mapping identified loci associated with interim plasma idelalisib concentration and the other 3 treatment-related endpoints. Thirteen priority candidate quantitative trait genes identified in CC mice may now guide interrogation of risk factors for adverse drug responses associated with idelalisib in humans.

PubMed ID: 31501888 Exiting the NIEHS site

MeSH Terms: Animals; Antineoplastic Agents/blood; Antineoplastic Agents/toxicity*; Biomarkers/blood; Bronchoalveolar Lavage Fluid/cytology; Chemical and Drug Induced Liver Injury/blood; Chemical and Drug Induced Liver Injury/etiology; Chemical and Drug Induced Liver Injury/genetics*; Chromosome Mapping; Dose-Response Relationship, Drug; Liver Function Tests; Lung Injury/blood; Lung Injury/chemically induced; Lung Injury/genetics*; Mice, Inbred Strains; MicroRNAs/blood; Oxidative Stress; Phosphatidylinositol 3-Kinase/blood; Phosphatidylinositol 3-Kinase/toxicity*; Polymorphism, Single Nucleotide; Protein Kinase Inhibitors/blood; Protein Kinase Inhibitors/toxicity*; Purines; Quantitative Trait Loci/drug effects*; Quinazolinones; Risk Factors; Species Specificity; Toxicogenetics

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