{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T13:42:51Z","timestamp":1784641371209,"version":"3.55.0"},"reference-count":21,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T00:00:00Z","timestamp":1729728000000},"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":[[2024,12]]},"abstract":"<jats:p>Burosumab is approved for the treatment of hypophosphatemia in persistent tumor\u2010induced osteomalacia. This work exemplifies a model\u2010informed drug development approach that evaluated burosumab pharmacokinetics and pharmacokinetic\/pharmacodynamics in the ultrarare tumor\u2010induced osteomalacia population to support adult and pediatric dosing. Data from tumor\u2010induced osteomalacia participants were combined with data from X\u2010linked hypophosphatemia to understand pharmacokinetic and pharmacokinetic\/pharmacodynamic characteristics and covariates specific to tumor\u2010induced osteomalacia. Pharmacokinetic and pharmacokinetic\/pharmacodynamic simulations were performed using final models to support dosing recommendations for adults and extrapolation to pediatric patients. Burosumab pharmacokinetics were described using a one\u2010compartment model with first\u2010order absorption and body weight as a significant covariate. Pharmacokinetic\/pharmacodynamic relationships were described using a sigmoidal Emax model with significant covariates of baseline fibroblast growth factor 23 on baseline fasting serum phosphate and potency of burosumab response and tumor\u2010induced osteomalacia disease state resulting in a steep slope of response; however, the covariates are not clinically meaningful. Simulations demonstrated that, in pediatric patients, starting doses of burosumab 0.3 and 0.4\u2009mg\/kg every 2\u2009weeks at steady state would achieve normal serum phosphate levels in \u2265\u200930% of patients with relatively low risk of hyperphosphatemia (&lt;\u20093%). In adults, burosumab 0.3 and 0.5\u2009mg\/kg every 4\u2009weeks achieves similar percentages of responders and a relative low risk of hyperphosphatemia (&lt;\u20097%). Serum phosphate titration\u2010based burosumab dosing increased the probability of achieving normal serum phosphate levels. The models supported a model\u2010informed drug development approach for global approvals of titration\u2010based burosumab dosing, guided by monitoring fasting serum phosphate levels.<\/jats:p>","DOI":"10.1002\/cpt.3468","type":"journal-article","created":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T14:53:13Z","timestamp":1729781593000},"page":"1606-1614","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Model\u2010Informed Approach to Recommend Burosumab Dosing Regimens for Pediatric and Adult Patients With the Ultrarare Disease Tumor\u2010Induced Osteomalacia"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8260-6003","authenticated-orcid":false,"given":"Matthew W.","family":"Hruska","sequence":"first","affiliation":[{"name":"Kyowa Kirin Inc.  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamia","family":"Sid\u2010Otmane","sequence":"additional","affiliation":[{"name":"Certara Drug Development Solutions  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie H.","family":"Gosselin","sequence":"additional","affiliation":[{"name":"Certara Drug Development Solutions  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5868-9769","authenticated-orcid":false,"given":"Emilia","family":"Quattrocchi","sequence":"additional","affiliation":[{"name":"Kyowa Kirin Pharmaceutical Development Ltd  Marlow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun Ku","family":"Lee","sequence":"additional","affiliation":[{"name":"Morphic Therapeutic  Waltham Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Ann","family":"Mascelli","sequence":"additional","affiliation":[{"name":"Chinook Therapeutics Inc  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krina","family":"Mehta","sequence":"additional","affiliation":[{"name":"Kyowa Kirin Inc.  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9386-7732","authenticated-orcid":false,"given":"Suzanne M.","family":"Jan de Beur","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Marsteller","sequence":"additional","affiliation":[{"name":"Kyowa Kirin Inc.  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,10,24]]},"reference":[{"key":"e_1_2_13_1_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00267"},{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1530\/JME-20-0089"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-022-01005-8"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvab099"},{"key":"e_1_2_13_5_1","first-page":"3","article-title":"Tumour\u2010induced osteomalacia","volume":"13","author":"Minisola S.","year":"2017","journal-title":"Nat. Rev. Dis. Primers."},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm4.10580"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13593"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.4184"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.4233"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.570"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.611"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1950"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12161"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2105"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2014-2218"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.4331"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.2165\/11531280-000000000-00000"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2008.170"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.16609"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14030654"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-022-00987-9"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.3468","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T06:24:06Z","timestamp":1731651846000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.3468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,24]]},"references-count":21,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["10.1002\/cpt.3468"],"URL":"https:\/\/doi.org\/10.1002\/cpt.3468","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,24]]},"assertion":[{"value":"2024-05-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}