{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T06:07:26Z","timestamp":1778911646414,"version":"3.51.4"},"reference-count":16,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"abstract":"<jats:p>Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life\u2010threatening hematologic disorder driven by complement\u2010mediated destruction of red blood cells. Although complement inhibitors have transformed PNH management, clinical responses vary across therapeutic classes because intravascular and extravascular hemolysis contribute differently to disease manifestations. Existing quantitative systems pharmacology (QSP) models of the complement system have improved understanding of PNH dynamics but primarily represent intravascular hemolysis and therefore do not fully explain biomarker patterns observed with all available treatments. In this study, we extend a published QSP model of the alternative complement pathway to incorporate mechanisms of extravascular hemolysis. The updated model integrates clinical pharmacokinetic and pharmacodynamic data from phase III trials of C5, C3, and factor B inhibitors and characterizes biomarker responses, including lactate dehydrogenase and circulating hemoglobin. By capturing both intravascular and extravascular processes, the model reproduces differences in therapeutic effects across complement inhibitor classes and provides a more complete mechanistic representation of complement\u2010mediated hemolysis in PNH. The expanded model enables evaluation of drug targets throughout the complement cascade and supports prediction of biomarker dynamics, dose and regimen effects, and sources of patient variability. This work establishes a translational framework that can inform therapeutic development and guide the design of future studies for complement\u2010mediated diseases.<\/jats:p>","DOI":"10.1002\/cpt.70317","type":"journal-article","created":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T05:15:22Z","timestamp":1778908522000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systems Pharmacology Approach to Paroxysmal Nocturnal Hemoglobinuria: Quantitative Framework for Biomarker Dynamics across Multi\u2010Mechanistic Therapies"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4780-4984","authenticated-orcid":false,"given":"Allison","family":"Cruikshank","sequence":"first","affiliation":[{"name":"Mathematics Department Duke University  Durham North Carolina USA"},{"name":"Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8982-4863","authenticated-orcid":false,"given":"Yuching","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4801-1919","authenticated-orcid":false,"given":"Guansheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Pharmacometrics Translational Sciences, Eisai Co., Ltds  Nutley New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5755-3904","authenticated-orcid":false,"given":"Jiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3858-2048","authenticated-orcid":false,"given":"Hao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"e_1_2_11_1_1","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/978-90-481-9485-8_22","article-title":"Epidemiology of rare anaemias in Europe","volume":"686","author":"Gulbis B.","year":"2010","journal-title":"Adv. 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Biol."},{"key":"e_1_2_11_7_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.blre.2023.101041","article-title":"Biomarkers and laboratory assessments for monitoring the treatment of patients with paroxysmal nocturnal hemoglobinuria: differences between terminal and proximal complement inhibition","volume":"59","author":"Kulasekararaj A.G.","year":"2023","journal-title":"Blood Rev."},{"key":"e_1_2_11_8_1","unstructured":"Administration USFaD.Soliris (eculizumab) Prescribing Information(2017) Report No.: BLA 125166."},{"key":"e_1_2_11_9_1","unstructured":"Agency E.M.Ultomiris (ravulizumab): European Public Assessment Report(2019) Report No.: EMA\/CHMP\/220699\/2019."},{"key":"e_1_2_11_10_1","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1111\/bcp.16394","article-title":"Pharmacokinetic characterization and exposure\u2010response relationship of crovalimab in the COMMODORE 1, 2 and 3 and COMPOSER trials of patients with paroxysmal nocturnal haemoglobinuria","volume":"91","author":"Cosson V.","year":"2025","journal-title":"Br. J. Clin. Pharmacol."},{"key":"e_1_2_11_11_1","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1007\/s40268-024-00500-7","article-title":"Population pharmacokinetic and pharmacokinetic\/pharmacodynamic analyses of Pegcetacoplan in patients with paroxysmal nocturnal Hemoglobinuria","volume":"24","author":"Crass R.L.","year":"2024","journal-title":"Drugs R D."},{"key":"e_1_2_11_12_1","volume-title":"Integrated Review: NDA 218037","author":"Administration USFaD","year":"2024"},{"key":"e_1_2_11_13_1","doi-asserted-by":"crossref","first-page":"4936","DOI":"10.1182\/bloodadvances.2024015490","article-title":"Characterizing clinically significant extravascular hemolysis in adults with PNH on ravulizumab or eculizumab treatment","volume":"9","author":"Kulasekararaj A.G.","year":"2025","journal-title":"Blood Adv."},{"key":"e_1_2_11_14_1","first-page":"704","article-title":"Understanding pharmacological complement inhibition in paroxysmal nocturnal hemoglobinuria","volume":"109","author":"Risitano A.M.","year":"2024","journal-title":"Haematologica"},{"key":"e_1_2_11_15_1","doi-asserted-by":"crossref","first-page":"578","DOI":"10.3389\/fphys.2019.00578","article-title":"Red blood cell homeostasis and altered vesicle formation in patients with paroxysmal nocturnal Hemoglobinuria","volume":"10","author":"Freitas Leal J.K.","year":"2019","journal-title":"Front. Physiol."},{"key":"e_1_2_11_16_1","doi-asserted-by":"crossref","first-page":"3699","DOI":"10.1182\/blood-2005-04-1717","article-title":"Diagnosis and management of paroxysmal nocturnal hemoglobinuria","volume":"106","author":"Parker C.","year":"2005","journal-title":"Blood"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70317","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70317","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70317","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T05:15:26Z","timestamp":1778908526000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70317"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,15]]},"references-count":16,"alternative-id":["10.1002\/cpt.70317"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70317","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,15]]},"assertion":[{"value":"2026-02-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cpt.70317"}}