{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:21:21Z","timestamp":1791937281760,"version":"4.3.4"},"reference-count":26,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T00:00:00Z","timestamp":1640044800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012112","name":"Swedish Orphan Biovitrum","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012112","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>Primary haemophagocytic lymphohistiocytosis (HLH) is a rare, life\u2010threatening, hyperinflammatory syndrome generally occurring in early childhood. The monoclonal antibody emapalumab binds and neutralises <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.guidetopharmacology.org\/GRAC\/LigandDisplayForward?ligandId=4968\">interferon \u03b3<\/jats:ext-link> (IFN\u03b3). This study aimed to determine an emapalumab dosing regimen when traditional dose\u2010finding approaches are not applicable, using pharmacokinetic\u2010pharmacodynamic analyses to further clarify HLH pathogenesis and confirm IFN\u03b3 neutralisation as the relevant therapeutic target in pHLH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Initial emapalumab dosing (1\u00a0mg\/kg) for pHLH patients participating in a pivotal multicentre, open\u2010label, single\u2010arm, phase 2\/3 study was based on anticipated IFN\u03b3 levels and allometrically scaled pharmacokinetic parameters estimated in healthy volunteers. Emapalumab dosing was adjusted based on estimated IFN\u03b3\u2010mediated clearance and HLH clinical and laboratory criteria. Frequent dosing and emapalumab dose adaptation were used to account for highly variable IFN\u03b3 levels and potential target\u2010mediated drug disposition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>High inter\u2010 and intra\u2010individual variability in IFN\u03b3 production (assessed by total IFN\u03b3 levels, range: 10<jats:sup>2<\/jats:sup>\u201010<jats:sup>6<\/jats:sup>\u00a0pg\/mL) was observed in pHLH patients. Administering emapalumab reduced IFN\u03b3 activity, resulting in significant improvements in clinical and laboratory parameters and a reduced risk of adverse events, mainly related to pHLH. Modelled outcomes supported dose titration starting from 1\u00a0mg\/kg, with possible increases to 3, 6 or 10\u00a0mg\/kg based on re\u2010evaluation of parameters of disease activity every 3\u00a0days.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The variable and unanticipated extremely high IFN\u03b3 concentrations in patients with pHLH are reflected in parameters of disease activity. Improved outcomes can be achieved by neutralising IFN\u03b3 using frequent emapalumab dosing and dose adaptation guided by clinical and laboratory observations.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15133","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T15:50:15Z","timestamp":1635436215000},"page":"2128-2139","source":"Crossref","is-referenced-by-count":38,"title":["Emapalumab in primary haemophagocytic lymphohistiocytosis and the pathogenic role of interferon gamma: A pharmacometric model\u2010based approach"],"prefix":"10.1111","volume":"88","author":[{"given":"Philippe","family":"Jacqmin","sequence":"first","affiliation":[{"name":"MnS Modelling and Simulation  Dinant Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Laveille","sequence":"additional","affiliation":[{"name":"Calvagone Sarl  Liergues France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Snoeck","sequence":"additional","affiliation":[{"name":"Luccio BV  Meerhout Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Jordan","sequence":"additional","affiliation":[{"name":"Divisions of Immunobiology and Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics Cincinnati Children's Hospital Medical Center  Cincinnati OH USA"},{"name":"University of Cincinnati College of Medicine  Cincinnati OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Locatelli","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Sapienza University of Rome  Rome Italy"},{"name":"Department of Pediatric Hematology\u2010Oncology and Cell and Gene Therapy IRCCS Bambino Ges\u00f9 Children's Hospital  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Ballabio","sequence":"additional","affiliation":[{"name":"Swedish Orphan Biovitrum AG (Sobi)  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"de Min","sequence":"additional","affiliation":[{"name":"Swedish Orphan Biovitrum AG (Sobi)  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12,21]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-03-278127"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2019.00435"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-01-0172"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-06-356261"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.10.068"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-788349"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2018.05.031"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2016.07.023"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-10-3413"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.200900009"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.1991.tb11878.x"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2011.11.046"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2010.158"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-209020"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.07.021"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2012.06.257"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1911326"},{"key":"e_1_2_10_19_1","unstructured":"US Food and Drug Administration.Denter for Drug Evaluation Research. 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