{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T15:58:14Z","timestamp":1770393494309,"version":"3.49.0"},"reference-count":47,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T00:00:00Z","timestamp":1652832000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:p>Severe neutropenia is the major dose\u2010liming toxicity of irinotecan\u2010based chemotherapy. The objective was to assess to what extent a population pharmacokinetic\/pharmacodynamic model including patient\u2010specific demographic\/clinical characteristics, individual pharmacokinetics, and absolute neutrophil counts (ANCs) can predict irinotecan\u2010induced grade 4 neutropenia. A semimechanistic population pharmacokinetic\/pharmacodynamic model was developed to describe neutrophil response over time in 197 patients with cancer receiving irinotecan. For covariate analysis, sex, race, age, pretreatment total bilirubin, and body surface area were evaluated to identify significant covariates on system\u2010related parameters (mean transit time (MTT) and \u0263) and sensitivity to neutropenia effects of irinotecan and SN\u201038 (SLOPE). The model\u2010based simulation was performed to assess the contribution of the identified covariates, individual pharmacokinetics, and baseline ANC alone or with incremental addition of weekly ANC up to 3\u00a0weeks on predicting irinotecan\u2010induced grade 4 neutropenia. The time course of neutrophil response was described using the model assuming that irinotecan and SN\u201038 have toxic effects on bone marrow proliferating cells. Sex and pretreatment total bilirubin explained 10.5% of interindividual variability in MTT. No covariates were identified for SLOPE and \u03b3. Incorporating sex and pretreatment total bilirubin (area under the receiver operating characteristic curve (AUC\u2010ROC): 50%, 95% CI 50\u201350%) or with the addition of individual pharmacokinetics (AUC\u2010ROC: 62%, 95% CI 53\u201371%) in the model did not result in accurate prediction of grade 4 neutropenia. However, incorporating ANC only at baseline and week 1 in the model achieved a good prediction (AUC\u2010ROC: 78%, 95% CI 69\u201388%). These results demonstrate the potential applicability of a model\u2010based approach to predict irinotecan\u2010induced neutropenia, which ultimately allows for personalized intervention to maximize treatment outcomes.<\/jats:p>","DOI":"10.1002\/cpt.2621","type":"journal-article","created":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T12:09:55Z","timestamp":1650888595000},"page":"316-326","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Model\u2010Based Prediction of Irinotecan\u2010Induced Grade 4 Neutropenia in Advanced Cancer Patients: Influence of Demographic and Clinical Factors"],"prefix":"10.1111","volume":"112","author":[{"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":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ron H. J.","family":"Mathijssen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Erasmus MC Cancer Institute  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ron H. N.","family":"van Schaik","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry Erasmus MC  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Innocenti","sequence":"additional","affiliation":[{"name":"Oncology Early Development AbbVie, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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 Computational and Data Sciences University at Buffalo State University of New York at Buffalo  Buffalo New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,5,18]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-018-0644-7"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1993.11.11.2194"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1996.14.11.2959"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2003.08.058"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2008.0012"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-8049(99)00259-2"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2002.20.1.7"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.11882"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1200\/OP.21.00624"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.07.173"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djm115"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-1122"},{"key":"e_1_2_11_14_1","unstructured":"Pfizer CAMPTOSAR\u00ae(irinotecan HCl) Prescribing Information<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2014\/020571s048lbl.pdf> (2014). Accessed April 10 2022."},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-021-03024-w"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2020.09.007"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.23.6125"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.20.6300"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/tpj.2016.75"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270006295060"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2008.05.002"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2002.02.140"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.55.2307"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.tpj.6500072"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-1526"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djh298"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.11-8-944"},{"key":"e_1_2_11_28_1","unstructured":"Monolix 2018R1 User guide.Monolix 2017<http:\/\/monolix.lixoft.com\/single\u2010page\/> (2019). Accessed April 10 2022."},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-021-01589-2"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-4145-2"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1214\/14-EJS890"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-011-1769-7"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781118548387"},{"key":"e_1_2_11_34_1","first-page":"2182","article-title":"Clinical pharmacokinetics and metabolism of irinotecan (CPT\u201011)","volume":"7","author":"Mathijssen R.H.","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-0815"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI108517"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2013.12.006"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.25691"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-021-00086-8"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15397-4"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcibr2013250"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2020.03.034"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdr493"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/tpj.2012.24"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmpb.2008.10.011"},{"key":"e_1_2_11_46_1","unstructured":"US Food and Drug Administration Project Optimus<https:\/\/www.fda.gov\/about\u2010fda\/oncology\u2010center\u2010excellence\/project\u2010optimus> (2022). Accessed April 10 2022."},{"issue":"1","key":"e_1_2_11_47_1","first-page":"S36","article-title":"Status toward the implementation of precision dosing in children","volume":"61","author":"Barrett J.S.","year":"2021","journal-title":"J. Clin. Pharmacol."},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12588"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2621","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.2621","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2621","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T13:27:45Z","timestamp":1699363665000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.2621"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,18]]},"references-count":47,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["10.1002\/cpt.2621"],"URL":"https:\/\/doi.org\/10.1002\/cpt.2621","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,18]]},"assertion":[{"value":"2022-02-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}