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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.<\/jats:p>","DOI":"10.1093\/toxsci\/kfz199","type":"journal-article","created":{"date-parts":[[2019,9,5]],"date-time":"2019-09-05T19:27:15Z","timestamp":1567711635000},"page":"265-278","source":"Crossref","is-referenced-by-count":28,"title":["Identification of Candidate Risk Factor Genes for Human Idelalisib Toxicity Using a Collaborative Cross Approach"],"prefix":"10.1093","volume":"172","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1968-6666","authenticated-orcid":false,"given":"Merrie","family":"Mosedale","sequence":"first","affiliation":[{"name":"Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina 27709"},{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599"},{"name":"Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3950-3794","authenticated-orcid":false,"given":"Yanwei","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Genetics"},{"name":"Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Scott","family":"Eaddy","sequence":"additional","affiliation":[{"name":"Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W","family":"Corty","sequence":"additional","affiliation":[{"name":"Department of Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manisha","family":"Nautiyal","sequence":"additional","affiliation":[{"name":"Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9541-8917","authenticated-orcid":false,"given":"Paul B","family":"Watkins","sequence":"additional","affiliation":[{"name":"Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina 27709"},{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2419-0430","authenticated-orcid":false,"given":"William","family":"Valdar","sequence":"additional","affiliation":[{"name":"Department of Genetics"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,9,14]]},"reference":[{"key":"2019112509003772500_kfz199-B1","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1016\/j.cellsig.2015.09.003","article-title":"VCAM-1 is a TGF-beta1 inducible gene upregulated in idiopathic pulmonary fibrosis","volume":"27","author":"Agassandian","year":"2015","journal-title":"Cell. 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