{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:45:24Z","timestamp":1791409524735,"version":"4.3.3"},"reference-count":33,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T00:00:00Z","timestamp":1702857600000},"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":[[2024,9]]},"abstract":"<jats:p>\n                    Hydroxyurea treatment for children with sickle cell anemia (SCA) is effective and life\u2010saving. Stepwise escalation to maximum tolerated dose (MTD) provides optimal benefits, but is logistically challenging and time\u2010consuming, especially in low\u2010income countries where most people with SCA live. Model\u2010informed precision dosing (MIPD) of hydroxyurea expedites MTD determination and improves outcomes compared with trial\u2010and\u2010error dose adjustments. HdxSim, a user\u2010friendly, online, clinical decision support tool was developed to facilitate hydroxyurea MIPD and evaluated using real\u2010world pharmacokinetic (PK) data. First\u2010dose hydroxyurea PK profiles were analyzed from two clinical trial datasets (Hydroxyurea Study of Long\u2010Term Effects (HUSTLE), NCT00305175 and Therapeutic Response Evaluation and Adherence Trial (TREAT), NCT02286154). Areas under the concentration\u2010time curve (AUC) estimated by HdxSim were compared with those determined using traditional trapezoidal methodology and PK software (MWPharm\u2010DOS). The doses predicted by HdxSim and MWPharm\u2010DOS were compared with the observed clinical MTD. For HUSTLE participants, HdxSim accurately estimated hydroxyurea AUC compared with the trapezoidal method, with &lt;\u200920% variance. The average (mean\u2009\u00b1\u2009SD) AUC for TREAT participants estimated with HdxSim (68.6\u2009\u00b1\u200918.0\u2009mg*hour\/L) was lower than MWPharm\u2010DOS (78.6\u2009\u00b1\u200920.7\u2009mg*hour\/L,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.012), but the average recommended doses were not different (425 vs. 423\u2009mg\/day,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.97). Moreover, HdxSim was non\u2010inferior to MWPharm\u2010DOS at predicting clinical MTD (absolute difference 3.9\u2009\u00b1\u20095.8 vs. 4.9\u2009\u00b1\u20098.2\u2009mg\/kg\/day,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.19). HdxSim accurately estimates hydroxyurea exposure and is noninferior to traditional PK approaches at predicting the clinical hydroxyurea MTD. Hydroxyurea dosing based on target exposure leads to improved outcomes in children with SCA, and has the potential to make PK\u2010guided hydroxyurea dosing more accessible to this neglected population globally.\n                  <\/jats:p>","DOI":"10.1002\/cpt.3119","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T02:58:32Z","timestamp":1701226712000},"page":"670-677","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Rationale, Development, and Validation of\n                    <scp>HdxSim<\/scp>\n                    , a Clinical Decision Support Tool for Model\u2010Informed Precision Dosing of Hydroxyurea for Children with Sickle Cell Anemia"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5823-0218","authenticated-orcid":false,"given":"Alexandra","family":"Power\u2010Hays","sequence":"first","affiliation":[{"name":"Division of Hematology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati  Cincinnati Ohio USA"},{"name":"Global Health Center Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8552-8298","authenticated-orcid":false,"given":"Min","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati  Cincinnati Ohio USA"},{"name":"Division of Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7655-6094","authenticated-orcid":false,"given":"Nieko","family":"Punt","sequence":"additional","affiliation":[{"name":"Medimatics  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8471-9826","authenticated-orcid":false,"given":"Tomoyuki","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati  Cincinnati Ohio USA"},{"name":"Division of Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4083-0060","authenticated-orcid":false,"given":"Luke R.","family":"Smart","sequence":"additional","affiliation":[{"name":"Division of Hematology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati  Cincinnati Ohio USA"},{"name":"Global Health Center Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4224-2967","authenticated-orcid":false,"given":"Alexander A.","family":"Vinks","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati  Cincinnati Ohio USA"},{"name":"Division of Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9582-0594","authenticated-orcid":false,"given":"Russell E.","family":"Ware","sequence":"additional","affiliation":[{"name":"Division of Hematology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati  Cincinnati Ohio USA"},{"name":"Global Health Center Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12,18]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)30193-9"},{"key":"e_1_2_10_2_1","unstructured":"World Health Organization (WHO).Sickle\u2010cell anaemia. Report by the secretariat(2006)https:\/\/apps.who.int\/gb\/ebwha\/pdf_files\/WHA59\/A59_R20\u2010en.pdfAccessed December 6 2020."},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(23)00118-7"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.semperi.2015.03.008"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61229-X"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-020-01557-2"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0000000000000582"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.28969"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-04-146852"},{"key":"e_1_2_10_10_1","unstructured":"Kenya Paediatric Research Consortium.National guidelines for control and management of sickle cell disease in Kenya. <https:\/\/ncdak.org\/wp\u2010content\/uploads\/2021\/07\/NATIONAL\u2010GUIDELINES\u2010FOR\u2010CONTROL\u2010AND\u2010MANAGEMENT\u2010OF\u2010SICKLE\u2010CELL\u2010DISEASE\u2010IN\u2010KENYA\u2010.pdf> (2020) Accessed May 18 2023."},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)78941-8"},{"key":"e_1_2_10_12_1","volume-title":"The Selection and Use of Essential Medicines 2023: Executive Summary of the Report of the 24th WHO Expert Committee on the Selection and Use of Essential Medicines, 24\u201328 April 2023","author":"Web Annex A","year":"2023"},{"key":"e_1_2_10_13_1","volume-title":"The Selection and Use of Essential Medicines 2023: Executive Summary of the Report of the 24th WHO Expert Committee on the Selection and Use of Essential Medicines, 24\u201328 April 2023","author":"Web Annex B","year":"2023"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60355-3"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199505183322001"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2022-160485"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2000146"},{"key":"e_1_2_10_18_1","first-page":"125","article-title":"Long\u2010term hydroxyurea treatment in children with sickle cell disease: tolerance and clinical outcomes","volume":"91","author":"De Montalembert M.","year":"2006","journal-title":"Haematologica"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-07-364190"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12851"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2028"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-07-2475"},{"key":"e_1_2_10_23_1","first-page":"1550","article-title":"Safety of hydroxyurea in children with sickle cell anemia: results of the HUG\u2010KIDS study, a phase I\/II trial, Pediatric Hydroxyurea Group","volume":"94","author":"Kinney T.R.","year":"1999","journal-title":"Blood"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25510"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.765958"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.17663"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00620"},{"key":"e_1_2_10_28_1","first-page":"679","article-title":"Determination of hydroxyurea in mammalian tissues and blood","volume":"16","author":"Fabricius E.","year":"1971","journal-title":"Rev. Eur. Etud. Clin. Biol."},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2017.08.009"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12684"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-4825(92)90011-B"},{"key":"e_1_2_10_32_1","volume-title":"The Basic Practice of Statistics","author":"Moore D.","year":"2013"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2023.1130206"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.3119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T05:39:19Z","timestamp":1755149959000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.3119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,18]]},"references-count":33,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,9]]}},"alternative-id":["10.1002\/cpt.3119"],"URL":"https:\/\/doi.org\/10.1002\/cpt.3119","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,18]]},"assertion":[{"value":"2023-09-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}