{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T14:37:54Z","timestamp":1769006274729,"version":"3.49.0"},"reference-count":44,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T00:00:00Z","timestamp":1738022400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:p>Daprodustat, a novel oral hypoxia\u2010inducible factor prolyl hydroxylase inhibitor is approved in the United States for the treatment of anemia due to chronic kidney disease (CKD) in adults receiving dialysis for at least 4\u2009months. Pharmacodynamic dose\u2010hemoglobin (Dose\u2010Hgb) models were developed as daprodustat progressed through development. To support global phase III development, a dose\u2010titration algorithm, guided by simulations from the initial Dose\u2010Hgb model based on phase II clinical data, was implemented. This work was to update and re\u2010calibrate this model to support the dose titration algorithm. Data from five pivotal phase III studies in CKD patients with anemia treated with daprodustat once daily (q.d.) and\/or three times a week (t.i.w.) using a titration dosing schedule were included. The data comprised 2,770 CKD patients with anemia providing 53,535 Hgb observations over a period of 6\u2009months up to 4\u2009years. This final Dose\u2010Hgb model consisted of a precursor cell compartment and 12 transit compartments to describe the red blood cell (RBC) lifespan. Treatment increased the precursor cell production rate (<jats:italic>K<\/jats:italic><jats:sub>in<\/jats:sub>) by a power of allometrically scaled dose. Disease progression, as an exponential decline of Hgb production rate over time, varied with dialysis status. The dose\u2010titration algorithm resulted in comparable response for t.i.w. dosing relative to q.d. dosing. Titration\u2010based visual predictive checks for Hgb target criteria for the analysis dataset and the prediction dataset showed that the model adequately predicted the observed data. This re\u2010calibrated Dose\u2010Hgb model will provide further support for the individualized dosing strategy in CKD patients with anemia treated with daprodustat.<\/jats:p>","DOI":"10.1002\/cpt.3544","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T05:33:56Z","timestamp":1738128836000},"page":"846-856","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrated Longitudinal Population Dose\u2010Hemoglobin Response of Daprodustat Following Dose Titration in Patients With Anemia in Chronic Kidney Disease"],"prefix":"10.1002","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7698-2149","authenticated-orcid":false,"given":"Kelly M.","family":"Mahar","sequence":"first","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7016-2846","authenticated-orcid":false,"given":"Martijn","family":"van Noort","sequence":"additional","affiliation":[{"name":"Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&amp;P)  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&amp;P)  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9841-2342","authenticated-orcid":false,"given":"Shuying","family":"Yang","sequence":"additional","affiliation":[{"name":"GSK  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2186-7195","authenticated-orcid":false,"given":"Sandra A. G.","family":"Visser","sequence":"additional","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"},{"name":"Alltrna  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9183-2678","authenticated-orcid":false,"given":"Teun M.","family":"Post","sequence":"additional","affiliation":[{"name":"Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&amp;P)  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,1,28]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2002.00299.x"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084943"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00041552-200205000-00011"},{"key":"e_1_2_9_4_1","volume-title":"USRDS Annual Data Report: Epidemiology of Kidney Disease in the United States","author":"United States Renal Data System","year":"2023"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V132504"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/ckj\/sfab195"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.23876\/j.krcp.20.020"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12882-022-02778-8"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfaa142.P0865"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.07780812"},{"key":"e_1_2_9_11_1","volume-title":"Package Insert","author":"Jesduvroq","year":"2023"},{"key":"e_1_2_9_12_1","first-page":"105","article-title":"Recommendations by the Asian pacific society of nephrology (apsn) on the appropriate use of hif\u2010ph inhibitors","volume":"26","author":"Yap D.Y.H.","year":"2020","journal-title":"Nephrol. Ther."},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2016.12.011"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.2147\/TCRM.S293879"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.07.019"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfv302"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270010377201"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1208\/aapsj080364"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-018-9606-9"},{"key":"e_1_2_9_20_1","article-title":"Population dose\u2010response analysis of hemoglobin data from global phase 2 and Japanese phase 3 studies with daprodustat in chronic kidney disease patients with anemia following once daily (QD) or 3 times weekly (TIW) administration","volume":"109","author":"Van den Berg P.","year":"2021","journal-title":"Clin. Pharmacol. Ther."},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1159\/000328060"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1029"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-012-9261-5"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2011.03.031"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.527"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270010376965"},{"key":"e_1_2_9_27_1","unstructured":"Goulooze S.C. vanNoort M.&van denBerg P.Innovative adaptive dose simulations in NONMEM to allow simulation based model evaluation of titration based dosing applied to a population dose hemoglobin model for daprodustatIn American Conference on Pharmacometrics (ACoP)."},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1208\/ps040427"},{"key":"e_1_2_9_29_1","unstructured":"Beal S. Boeckmann L. Bauer R.&Sheiner L.NONMEM User's Guides. (1989\u20132009)(2009)."},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmpb.2005.04.005"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmpb.2003.11.003"},{"key":"e_1_2_9_32_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2021"},{"key":"e_1_2_9_33_1","unstructured":"RStudio.RStudio: Integrated Development Environment for R<https:\/\/www.rstudio.com\/>. (Boston MA 2020)."},{"key":"e_1_2_9_34_1","unstructured":"Savic R.Improved Pharmacometric Model Building Techniques Doctoral Thesis Comprehensive Summary Acta Universitatis Upsaliensis (2008)."},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2023.02.019"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.00550122"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/ckj\/sfy013"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfab065"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfab318"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.83"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-024-01417-9"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1177\/14791641211013734"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V95.8.2514"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-7843.2005.pto960310.x"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.3544","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T09:25:14Z","timestamp":1741771514000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.3544"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,28]]},"references-count":44,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1002\/cpt.3544"],"URL":"https:\/\/doi.org\/10.1002\/cpt.3544","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,28]]},"assertion":[{"value":"2024-06-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}