{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T00:00:24Z","timestamp":1794009624563,"version":"4.8.0"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T00:00:00Z","timestamp":1638144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare and life\u2010threatening autoimmune thrombotic microangiopathy. Caplacizumab, evaluated in phase II and III studies in adults, shortens the time to platelet count response and reduces aTTP exacerbations, has a favorable safety profile, and can potentially reduce refractoriness and mortality associated with aTTP. Since no children with aTTP were enrolled in these clinical trials, caplacizumab has been initially approved for use only in adult patients with aTTP (10 mg). Pediatric dosing recommendations were developed using model\u2010based simulations. A semimechanistic pharmacokinetic\/pharmacodynamic population model has been developed describing the interaction between caplacizumab and von Willebrand factor antigen (vWF:Ag) following intravenous and subcutaneous administration of caplacizumab in different adult populations, at various dose levels, using nonlinear mixed\u2010effects modeling. Based on the allometrically scaled pharmacokinetic\/pharmacodynamic model, different dosing regimens were simulated in 8000 children (aged 2\u201018 years). Simulated caplacizumab exposures and vWF:Ag levels across different age categories were compared to an adult reference group. A simulated daily dose of 5 mg in children weighing &lt;40 kg and of 10 mg in children weighing \u226540 kg resulted in similar exposures and vWF:Ag suppression across age and weight groups. Despite the lack of pediatric clinical data, the results of this modeling and simulation analysis constituted the basis for the European extension of indication for caplacizumab (10 mg) to adolescents aged &gt;12 years and with a body weight \u226540 kg. This represents a rare case in which regulatory authorities have deemed a modeling and simulation study robust enough to approve a variation of indication.<\/jats:p>","DOI":"10.1002\/jcph.1991","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T11:40:50Z","timestamp":1635248450000},"page":"409-421","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Caplacizumab Model\u2010Based Dosing Recommendations in Pediatric Patients With Acquired Thrombotic Thrombocytopenic Purpura"],"prefix":"10.1002","volume":"62","author":[{"given":"Martin","family":"Bergstrand","sequence":"first","affiliation":[{"name":"Pharmetheus AB  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Hansson","sequence":"additional","affiliation":[{"name":"Pharmetheus AB  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Delaey","sequence":"additional","affiliation":[{"name":"Sanofi  Diegem Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip","family":"Callewaert","sequence":"additional","affiliation":[{"name":"Sanofi  Diegem Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"De Passos Sousa","sequence":"additional","affiliation":[{"name":"Sanofi  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Laura","family":"Sargentini\u2010Maier","sequence":"additional","affiliation":[{"name":"Sanofi  Diegem Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcna.2016.09.010"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2008.07276.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24612"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2019.1607293"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajhp\/zxaa151"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-01-550244"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/rth2.12160"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.13107"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/2040620720902904"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lpm.2011.10.024"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-10-709857"},{"key":"e_1_2_10_13_1","unstructured":"Sargentini\u2010MaierB.Caplacizumab dosing rational in aTTP patients supported by mechanism based PKPD modelling. PAGE 28 (2019) Abstr 8800 [www.page\u2010meeting.org\/?abstract=8800].https:\/\/www.page\u2010meeting.org\/?abstract=8800. Accessed January 19 2021."},{"key":"e_1_2_10_14_1","unstructured":"Sanofi: Cablivi(TM) (caplacizumab) approved in Europe for adults with acquired thrombotic thrombocytopenic purpura (aTTP) \u2010 Sanofi.https:\/\/www.sanofi.com\/en\/media\u2010room\/press\u2010releases\/2018\/2018\u201009\u201003\u201007\u201000\u201000. Accessed January 12 2021."},{"key":"e_1_2_10_15_1","unstructured":"Sanofi: FDA approves Cablivi\u00ae (caplacizumab\u2010yhdp) the first Nanobody\u00ae\u2010based medicine for adults with acquired thrombotic thrombocytopenic purpura (aTTP) \u2010 Sanofi.https:\/\/www.sanofi.com\/en\/media\u2010room\/press\u2010releases\/2019\/2019\u201002\u201006\u201017\u201043\u201021. Accessed January 12 2021."},{"key":"e_1_2_10_16_1","unstructured":"Ablynx.A Phase II Single\u2010Blind Randomized Placebo\u2010Controlled Trial to Study the Efficacy and Safety of Anti\u2010von Willebrand Factor Nanobody\u00ae Administered as Adjunctive Treatment to Patients With Acquired Thrombotic Thrombocytopenic Purpura.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01151423. Published2019. Accessed January 14 2021."},{"key":"e_1_2_10_17_1","unstructured":"Ablynx.A Phase III Double\u2010Blind Randomized Parallel Group Multicenter Placebo\u2010Controlled Trial to Study the Efficacy and Safety of Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02553317. Published2019. Accessed January 14 2021."},{"key":"e_1_2_10_18_1","unstructured":"Ablynx.Prospective Follow\u2010up Study for Patients Who Completed Study ALX0681\u2010C301 (HERCULES) to Evaluate Long\u2010Term Safety and Efficacy of Caplacizumab (Post\u2010HERCULES).https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02878603Published2020. Accessed January 14 2021."},{"key":"e_1_2_10_19_1","unstructured":"EMA assessment report: Cablivi.https:\/\/www.ema.europa.eu\/en\/documents\/assessment-report\/cablivi-epar-public-assessment-report_en.pdf. Published June 28 2018. Accessed January 12 2021."},{"key":"e_1_2_10_20_1","unstructured":"FDA NDA\/BLA Multi\u2010disciplinary Review and Evaluation {BLA 761112} {Caplacizumab (Cablivi\u00ae)}.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2019\/761112Orig1s000MultiR.pdf. Published February 5 2019. Accessed January 12 2021."},{"key":"e_1_2_10_21_1","unstructured":"EMA assessment report: Cablivi.https:\/\/www.ema.europa.eu\/en\/documents\/variation-report\/cablivi-h-c-4426-ii-0021-epar-assessment-report-variation_en.pdf. Published April 30 2020. Accessed January 18 2021."},{"key":"e_1_2_10_22_1","unstructured":"European Medicines Agency decision P\/0294\/2018 of 12 September 2018 on the acceptance of a modification of an agreed paediatric investigation plan for caplacizumab (EMEA\u2010001157\u2010PIP01\u201011\u2010M02). 8."},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.27737"},{"key":"e_1_2_10_24_1","article-title":"Real\u2010world evidence of caplacizumab use in the management of acute TTP [published online ahead of print November 4, 2020]","author":"Dutt T","journal-title":"Blood"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-019-04281-z"},{"key":"e_1_2_10_26_1","article-title":"Refractory acquired thrombotic thrombocytopenic purpura treated with caplacizumab in a pediatric patient with systemic lupus erythematosus [published online ahead of print 2021]","author":"Nagel MB","journal-title":"Pediatr Blood Cancer"},{"key":"e_1_2_10_27_1","article-title":"Immune\u2010mediated thrombotic thrombocytopenic purpura in childhood treated by caplacizumab, about 3 cases [published online ahead of print February 22, 2021]","author":"Boudali J","journal-title":"J Nephrol"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.HS9.0000567472.70005.67"},{"key":"e_1_2_10_29_1","first-page":"S_656\u2010S_656","article-title":"Abstract 2009: ALX\u20100081 a novel anti\u2010thrombotic: results of a single\u2010dose phase 1 study in healthy volunteers and further development in patients with stable angina undergoing PCI","volume":"118","author":"Jozef Bartunek","year":"2008","journal-title":"Circulation"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V114.22.1063.1063"},{"key":"e_1_2_10_31_1","unstructured":"Ablynx.A Phase I Single Center Open\u2010Label Randomized Single Dose Cross\u2010Over Study in Healthy Male Subjects to Investigate the Bioequivalence and Tolerability of Liquid and Reconstituted Lyophilized Subcutaneous Formulations of Caplacizumab.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02189733. Published2014. Accessed January 14 2021."},{"key":"e_1_2_10_32_1","unstructured":"Ablynx.A Phase 2 Randomized Open Label Clinical Trial in High Risk Percutaneous Coronary Intervention (PCI) Patients Receiving Standard Antithrombotic Treatment Plus Either ALX\u20100081 or GPIIb\/IIIa Inhibitor (ReoPro\u00ae) Over a Period of 24 Hours.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01020383. Published2019. Accessed January 14 2021."},{"key":"e_1_2_10_33_1","volume-title":"NONMEM User's Guides","author":"Beal SL","year":"2014"},{"key":"e_1_2_10_34_1","unstructured":"NHANES\u2013National health and nutrition examination survey homepage.https:\/\/www.cdc.gov\/nchs\/nhanes\/index.htm. Published December 18 2020. Accessed January 12 2021."},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1097\/MPH.0b013e3180308749"},{"key":"e_1_2_10_36_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Development Core Team"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(16)30125-9"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000992"},{"key":"e_1_2_10_39_1","unstructured":"EMA summary of product characteristics: Cablivi.https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/cablivi-epar-product-information_en.pdf. Published October 14 2020. Accessed January 15 2021."},{"key":"e_1_2_10_40_1","unstructured":"European Medicines Agency.EMA drug approval: Cablivi\u2010web page.https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/cablivi. Published September 17 2018. Accessed January 12 2021."},{"key":"e_1_2_10_41_1","unstructured":"FDA Drug Approval Package: CABLIVI\u2010web page.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2019\/761112Orig1s000TOC.cfm. Accessed January 12 2021."}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.1991","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcph.1991","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.1991","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T10:15:24Z","timestamp":1692958524000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.1991"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,29]]},"references-count":40,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022,3]]}},"alternative-id":["10.1002\/jcph.1991"],"URL":"https:\/\/doi.org\/10.1002\/jcph.1991","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,29]]},"assertion":[{"value":"2021-07-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-10-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}