Safety, Tolerability, and Pharmacokinetics of Adrenomedullin in Healthy Males: A Randomized, Double-Blind, Phase 1 Clinical Trial

Abstract

Background

Adrenomedullin (AM), an endogenous vasodilative peptide, has immunomodulative effects and acts as an accelerator of mucosal regeneration in the digestive tract. AM has shown beneficial effects in rodent models of inflammatory bowel disease and patients with ulcerative colitis. The present study aimed to evaluate the pharmacodynamic properties and safety of AM in healthy male adults in a phase 1 clinical trial.

Methods

This phase 1, randomized, double-blind, single-center study was conducted on healthy males aged 20–65 years. Subjects received either a placebo, 3 ng/kg/min AM, 9 ng/kg/min AM, or 15 ng/kg/min AM via continuous 12-h intravenous infusion. Other subjects received either placebo or 15 ng/kg/min AM for 8 h per day for 7 days. Adverse events (AEs), vital signs, physical examinations, laboratory tests, electrocardiograms (ECG), and pharmacokinetics were assessed.

Findings

All 24 subjects in the single-dose test completed the study. Of the 12 subjects in multiple dosing test, one from the AM group withdrew owing to a headache. No serious AEs were reported. Hemodynamic parameters were well maintained in all subjects. Slight ECG abnormalities were observed in the single-dose test. The plasma concentration of AM progressively increased in a dose-dependent manner and reached C_max at the end of administration. Plasma AM rapidly returned to baseline concentrations after termination, with a T_1/2 of under 60 min.

Interpretation

This is the first phase 1 trial in healthy men evaluating the safety of AM. Our results demonstrate the safety and tolerability of AM for subsequent Phase 2 trials.

Keywords:

• adrenomedullin
• Phase 1 clinical trial
• clinical pharmacology
• inflammatory bowel disease

Acknowledgement

We would like to thank Editage for English language editing.

Data Sharing Statement

The authors do not intend to share substantial data of this study, but they are ready to share the file of substantial data and all other study-related documents (in Japanese), at any specific time for any period, if the editorial board requires.

Disclosure

Kazuo Kitamura and Toshihiro Kita report a patent US 10335455 B2 issued. Kazuo Kitamura reports a patent PCT/JP2012/051010 licensed to Himura AM Pharma Corp.; holds stocks in Himuka AM Pharma Corp and is an advisor of Himura AM Pharma Corp. Toshihiro Kita holds stocks in Himuka AM Pharma Corp. The authors report no other conflicts of interest in this work.