{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T18:51:19Z","timestamp":1780599079069,"version":"3.54.1"},"reference-count":20,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T00:00:00Z","timestamp":1666051200000},"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":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Marzeptacog alfa (activated) (MarzAA) is an activated recombinant human FVII (rFVIIa) variant developed as subcutaneous (s.c.) administration for the treatment or prevention of bleeding episodes in patients with hemophilia A (HA) or hemophilia B (HB) with inhibitors and other rare bleeding disorders. Population pharmacokinetic (PK) modeling was applied for dose selection for a pivotal phase III clinical trial evaluating s.c. MarzAA for episodic treatment of spontaneous or traumatic bleeding episodes. The population PK model used MarzAA intravenous and s.c. data from previously completed clinical trials in patients with HA\/HB with or without inhibitors. Based on the model, clinical trial simulations were performed to predict MarzAA exposure after different dosing regimens. The exposure target was identified using an exposure\u2010matching strategy with a wild\u2010type rFVIIa but adjusting for the difference in potency between the two compounds. Simulations demonstrated a sufficient absorption rate and prolonged exposure following a single 60\u2009\u03bcg\/kg dose leading to 51% and 70% of the population reaching levels above the target after 3 and 6\u2009h, respectively. According to the phase III protocol, if a second dose was required after 3\u2009h because of a lack of efficacy, 90% of the population was observed to be above target 6\u2009h after the initial dose. The model\u2010informed drug development approach integrated information from several trials and guided dose selection in the pivotal phase III clinical trial for episodic treatment of an acute bleeding event in individuals with HA or HB with inhibitors without the execution of a phase II trial for that indication.<\/jats:p>","DOI":"10.1002\/psp4.12872","type":"journal-article","created":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T19:03:26Z","timestamp":1664823806000},"page":"1628-1637","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Phase III dose selection of marzeptacog alfa (activated) informed by population pharmacokinetic modeling: A\u00a0novel hemostatic drug"],"prefix":"10.1002","volume":"11","author":[{"given":"Alan","family":"Faraj","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Biosciences Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Knudsen","sequence":"additional","affiliation":[{"name":"Catalyst Biosciences  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shraddha","family":"Desai","sequence":"additional","affiliation":[{"name":"Catalyst Biosciences  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Neuman","sequence":"additional","affiliation":[{"name":"Catalyst Biosciences  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant E.","family":"Blouse","sequence":"additional","affiliation":[{"name":"Catalyst Biosciences  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3424-9686","authenticated-orcid":false,"given":"Ulrika S. H.","family":"Simonsson","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,18]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/rth2.12576"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40271-014-0075-y"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.2147\/JBM.S43734"},{"key":"e_1_2_10_5_1","unstructured":"CarcaoM GoudemandJ.Inhibitors in hemophilia: a primer.5th ed.World Federation of Hemophilia. November 2018 No. 7."},{"key":"e_1_2_10_6_1","unstructured":"FDA.Research C. for D. E. and The Voice of the Patient: A Series of Reports from FDA's Patient\u2010Focused Drug Development Initiative.2020. Accessed October 7 2022.https:\/\/www.fda.gov\/industry\/prescription\u2010drug\u2010user\u2010fee\u2010amendments\/fda\u2010led\u2010patient\u2010focused\u2010drug\u2010development\u2010pfdd\u2010public\u2010meetings"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.14247"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2007.03030.x"},{"key":"e_1_2_10_9_1","unstructured":"FDA.Research C. for B. E. and NovoSeven.2022. Accessed October 7 2022.https:\/\/www.fda.gov\/vaccines\u2010blood\u2010biologics\/blood\u2010blood\u2010products\/novoseven"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.48.113006.094708"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1208\/ps040427"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.13845"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2019-130559"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.13150"},{"key":"e_1_2_10_15_1","unstructured":"EMA NovoSeven.European Medicines Agency.2018. Accessed October 7 2022.https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/novoseven"},{"issue":"1","key":"e_1_2_10_16_1","first-page":"102","article-title":"Dosing and monitoring NovoSeven treatment","volume":"26","author":"Hedner U","year":"1996","journal-title":"Haemostasis"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1159\/000057294"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61139-2"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200106073442307"},{"key":"e_1_2_10_20_1","unstructured":"ISTH Congress Abstracts.Crimson 1: A Phase 3 study to evaluate the efficacy and safety of subcutaneous marzeptocog alfa (activated) for on\u2010demand treatment of bleed events in subjects with hemophilia A or B with inhibitors. Accessed October 7 2022.https:\/\/abstracts.isth.org\/abstract\/crimson\u20101\u2010a\u2010phase\u20103\u2010study\u2010to\u2010evaluate\u2010the\u2010efficacy\u2010and\u2010safety\u2010of\u2010subcutaneous\u2010marzeptocog\u2010alfa\u2010activated\u2010for\u2010on\u2010demand\u2010treatment\u2010of\u2010bleed\u2010events\u2010in\u2010subjects\u2010with\u2010hemophilia\u2010a\u2010or\u2010b\u2010with\u2010inhibitors\/"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-008-9094-4"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.12872","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.12872","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.12872","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T11:06:37Z","timestamp":1692443197000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.12872"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,18]]},"references-count":20,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["10.1002\/psp4.12872"],"URL":"https:\/\/doi.org\/10.1002\/psp4.12872","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,18]]},"assertion":[{"value":"2022-06-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}