{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T03:35:53Z","timestamp":1768016153021,"version":"3.49.0"},"reference-count":41,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2018,7,3]],"date-time":"2018-07-03T00:00:00Z","timestamp":1530576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Adrenomed AG"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2018,9]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Adrenomedullin (ADM) is an important regulator of endothelial barrier function and vascular tone, and may represent a novel treatment target in sepsis. The non\u2010neutralizing ADM antibody adrecizumab has shown promising results in preclinical sepsis models. In the present study, we investigated the safety, tolerability and pharmacokinetics (PK)\/pharmacodynamics of adrecizumab in a first\u2010in\u2010man study and in a second study during experimental human endotoxaemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Forty\u2010eight healthy male volunteers were enrolled in two randomized, double\u2010blind, placebo\u2010controlled phase I studies. In both studies, subjects received placebo or one of three doses of adrecizumab (<jats:italic>n<\/jats:italic> = 6 per group). In the second study, a bolus of 1\u00a0ng kg<jats:sup>\u20131<\/jats:sup> endotoxin was followed by infusion of 1\u00a0ng kg<jats:sup>\u20131<\/jats:sup> h<jats:sup>\u20131<\/jats:sup> endotoxin for 3\u00a0h to induce systemic inflammation, and the study medication infusion started 1\u00a0h after endotoxin bolus administration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Adrecizumab showed an excellent safety profile in both studies. PK analyses showed proportional increases in the maximum plasma concentration of adrecizumab with increasing doses, a small volume of distribution, a low clearance rate and a terminal half\u2010life of ~14\u00a0days. adrecizumab elicited a pronounced increase in plasma ADM levels, whereas levels of mid\u2010regional pro\u2010adrenomedullin remained unchanged, indicating that <jats:italic>de novo<\/jats:italic> synthesis of ADM was not influenced. In the second study, no effects of adrecizumab on cytokine clearance were observed, whereas endotoxin\u2010induced flu\u2010like symptoms resolved more rapidly.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Administration of adrecizumab is safe and well tolerated in humans, both in the absence and presence of systemic inflammation. These findings pave the way for further investigation of adrecizumab in sepsis patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.13655","type":"journal-article","created":{"date-parts":[[2018,6,1]],"date-time":"2018-06-01T16:18:32Z","timestamp":1527869912000},"page":"2129-2141","source":"Crossref","is-referenced-by-count":43,"title":["Safety, tolerability and pharmacokinetics\/pharmacodynamics of the adrenomedullin antibody adrecizumab in a first\u2010in\u2010human study and during experimental human endotoxaemia in healthy subjects"],"prefix":"10.1111","volume":"84","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6748-6090","authenticated-orcid":false,"given":"Christopher","family":"Geven","sequence":"first","affiliation":[{"name":"Department of Intensive Care Medicine, Radboud Center for Infectious Diseases (RCI) Radboud University Medical Center  HP: 710, PO Box 9101 6500 HB Nijmegen The 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Infectious Diseases (RCI) Radboud University Medical Center  HP: 710, PO Box 9101 6500 HB Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bas","family":"ten Elzen","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Medicine, Radboud Center for Infectious Diseases (RCI) Radboud University Medical Center  HP: 710, PO Box 9101 6500 HB Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandre","family":"Mebazaa","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, Burn and Critical Care University Hospitals Saint\u2010Louis \u2013 Lariboisi\u00e8re, AP\u2010HP  Paris France"},{"name":"UMR\u2010S 942, Inserm  Paris France"},{"name":"Sorbonne Paris Cit\u00e9 Paris Diderot University  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthijs","family":"Kox","sequence":"additional","affiliation":[{"name":"Department of Intensive Care 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