British Journal Of Clinical Pharmacology
Adrenomedullin (ADM) is an important regulator of endothelial barrier function and vascular tone, and may represent a novel treatment target in sepsis. The non-neutralizing ADM antibody Adrecizumab showed promising results in preclinical sepsis models. We investigated the safety, tolerability and pharmacokinetics/-dynamics of Adrecizumab in a first-in-man study and in a second study during experimental human endotoxemia. Forty-eight healthy male volunteers were enrolled in two randomized, double-blind, placebo-controlled phase I studies. In both studies, subjects received placebo or one out of three dosages of Adrecizumab (n=6 per group). In the second study, a bolus of 1 ng/kg endotoxin was followed by infusion of 1 ng/kg/hour endotoxin for 3 hours to induce systemic inflammation, and study medication infusion started one hour after endotoxin bolus administration. Adrecizumab showed an excellent safety profile in both studies. PK analyses showed proportional increases of the maximum plasma concentration of Adrecizumab with increasing dosages, a small volume of distribution, a low clearance rate and a terminal half-life of ~14 days. Adrecizumab elicited a pronounced increase of plasma ADM levels, while levels of mid-regional pro-adrenomedullin remained unchanged, indicating that de novo synthesis of ADM was not influenced. In the second study, no effects of Adrecizumab on cytokine clearance were observed, whereas endotoxin-induced flu-like symptoms resolved more rapidly. 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. This article is protected by copyright. All rights reserved.