{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:02:07Z","timestamp":1789340527642,"version":"build-2803163510"},"reference-count":31,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T00:00:00Z","timestamp":1707696000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T00:00:00Z","timestamp":1707696000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:p>\n                    Neutropenia is the major dose\u2010limiting toxicity of irinotecan\u2010based therapy. The objective of this study was to assess whether inclusion of germline genetic variants into a population pharmacokinetic\/pharmacodynamic model can improve prediction of irinotecan\u2010induced grade 4 neutropenia and identify novel variants of clinical value. A semimechanistic population pharmacokinetic\/pharmacodynamic model was used to predict neutrophil response over time in 197 patients receiving irinotecan. Covariate analysis was performed for demographic\/clinical factors and 4,781 genetic variants in 84 drug response\u2010 and toxicity\u2010related genes to identify covariates associated with neutrophil response. We evaluated the predictive value of the model for grade 4 neutropenia reflecting different clinical scenarios of available data on identified demographic\/clinical covariates, baseline and post\u2010treatment absolute neutrophil counts (ANCs), individual pharmacokinetics, and germline genetic variation. Adding 8 genetic identified covariates (rs10929302 (\n                    <jats:italic>UGT1A1<\/jats:italic>\n                    ), rs1042482 (\n                    <jats:italic>DPYD<\/jats:italic>\n                    ), rs2859101 (\n                    <jats:italic>HLA\u2010DQB3<\/jats:italic>\n                    ), rs61754806 (\n                    <jats:italic>NR3C1<\/jats:italic>\n                    ), rs9266271 (\n                    <jats:italic>HLA\u2010B<\/jats:italic>\n                    ), rs7294 (\n                    <jats:italic>VKORC1<\/jats:italic>\n                    ), rs1051713 (\n                    <jats:italic>ALOX5<\/jats:italic>\n                    ), and\n                    <jats:italic>ABCB1<\/jats:italic>\n                    rare variant burden) to a model using only baseline ANCs improved prediction of irinotecan\u2010induced grade 4 neutropenia from area under the receiver operating characteristic curve (AUC\u2010ROC) of 50\u201364% (95% confidence interval (CI), 54\u201374%). Individual pharmacokinetics further improved the prediction to 74% (95% CI, 64\u201384%). When weekly ANC was available, the identified covariates and individual pharmacokinetics yielded no additional contribution to the prediction. The model including only ANCs at baseline and at week 1 achieved an AUC\u2010ROC of 78% (95% CI, 69\u201388%). Germline DNA genetic variants may contribute to the prediction of irinotecan\u2010induced grade 4 neutropenia when incorporated into a population pharmacokinetic\/pharmacodynamic model. This approach is generalizable to drugs that induce neutropenia and ultimately allows for personalized intervention to enhance patient safety.\n                  <\/jats:p>","DOI":"10.1002\/cpt.3190","type":"journal-article","created":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T05:13:11Z","timestamp":1707714791000},"page":"1162-1174","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Model\u2010Based Prediction of Irinotecan\u2010Induced Grade 4 Neutropenia in Cancer Patients: Influence of Incorporating Germline Genetic Factors in the Model"],"prefix":"10.1002","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1381-4623","authenticated-orcid":false,"given":"Spinel","family":"Karas","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5667-5697","authenticated-orcid":false,"given":"Ron H. 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N.","family":"van Schaik","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry Erasmus MC University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Forrest","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5960-4034","authenticated-orcid":false,"given":"Tim","family":"Wiltshire","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3818-2252","authenticated-orcid":false,"given":"Robert R.","family":"Bies","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University at Buffalo School of Pharmacy and Pharmaceutical Sciences State University of New York at Buffalo  Buffalo New York USA"},{"name":"Institute for Artificial Intelligence and Data Sciences, University at Buffalo State University of New York at Buffalo  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9247-979X","authenticated-orcid":false,"given":"Federico","family":"Innocenti","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,12]]},"reference":[{"key":"e_1_2_9_1_1","first-page":"270","article-title":"All you need to know about UGT1A1 genetic testing for patients treated With irinotecan: a practitioner\u2010friendly guide","volume":"2100624","author":"Karas S.","year":"2021","journal-title":"JCO Oncol. 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