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

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.

Adrenomedullin for steroid-resistant ulcerative colitis: a randomized, double-blind, placebo-controlled phase-2a clinical trial

“…The increased plasma concentration of AM mostly returned to basal levels within 2 h after the termination of the AM infusion. We did not observe any progressive increase in the plasma concentration of AM after repeated administrations, which is a concern in multiple-dose administration studies in a phase 1 trial [ 15 ]. The AUC 0-10 h after 14 days of the three groups, namely 5, 10, and 15 ng/kg/min groups, was shown to be 152 ± 34, 281 ± 39, and 440 ± 191 h*pg/mL, respectively.…”

“…AM is thought to work as an endogenous counter-factor for UC, and thus, increases in AM production in UC patients were suggested. We found that the basal plasma concentration of AM was higher in patients with UC than that in healthy volunteers in the phase 1 single-dose study (11.4 ± 7.2 pg/mL ( n = 20) vs. 7.2 ± 1.4 pg/mL ( n = 23); P < 0.0001) [ 15 ]. Of note, in one UC patient in the present study, this value was found to be below the lower limit of quantification (< 5 pg/mL).…”

“…Briefly, AM is a peptide containing 52 amino acid residues with a ring structure formed by one intramolecular disulfide bond and an amidated structure formed by a C-terminal tyrosine [ 16 ]. We have produced a new lot of AM formulation for this phase 2 clinical trial utilizing the same manufacturing process according to the good manufacturing practice (GMP), as previously reported [ 15 ]. Briefly, the active pharmaceutical ingredient was chemically synthesized under GMP by the Peptide Institute (Osaka, Japan).…”

“…Serum concentrations of AM were assessed at predose, 4 and 8 h, and 2 h after administration (10 h after the start of drug administration) on 1, 8, and 14 days of the administration. Blood sampling and the procedures for the measurement of the AM concentration have been previously described [ 15 ]. Measurements and data processing were carried by the Bozo Research Centre (Tsukuba, Japan).…”

“…Additionally, as AM is an endogenous peptide, it would be expected to be safe for patients and could be added to existing drugs, such as steroids, immunosuppressants, and biologics. We have recently finished a phase 1 investigator-initiated clinical trial in healthy Japanese men and confirmed the safety and tolerability of AM [ 15 ]. After that, we have prepared a new AM formulation and planned a phase-2a investigator-initiated clinical trial for patients with intractable UC, due to the lack of support from industrial companies.…”