Article date: September 2018
By: Christopher Geven, Dirk Lier, Alice Blet, Roel Peelen, Bas Elzen, Alexandre Mebazaa, Matthijs Kox, Peter Pickkers in Volume 84, Issue 9, pages 2129-2141
Aims
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 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‐in‐man study and in a second study during experimental human endotoxaemia.
Methods
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 of three doses of adrecizumab (n = 6 per group). In the second study, a bolus of 1 ng kg–1 endotoxin was followed by infusion of 1 ng kg–1 h–1 endotoxin for 3 h to induce systemic inflammation, and the study medication infusion started 1 h after endotoxin bolus administration.
Results
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‐life of ~14 days. adrecizumab elicited a pronounced increase in plasma ADM levels, whereas 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.
Conclusions
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.
DOI: 10.1111/bcp.13655
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