Pharmacokinetics, safety and tolerability of the novel β‐hCG derived immunomodulatory compound, EA‐230

Abstract

Aims EA‐230 is a newly developed synthetic linear tetrapeptide (AQGV) derived from the chorionic gonadotropin hormone (β‐hCG). We investigated the pharmacokinetics, safety and tolerability of EA‐230 in healthy subjects using different administration strategies. Methods Double‐blind, randomized, placebo‐controlled, dose‐escalating phase I studies in healthy subjects using intravenous administration were conducted. In the single dosage study, 32 subjects were assigned to four single dosage groups (1, 3, 10 or 30 mg/kg). In the multiple dosage study, 24 subjects were assigned to three dosage groups (10, 20 or 30 mg/kg, thrice daily for 3 days). In the continuous dosage study, 24 subjects were assigned to three dosage groups (15, 30, or 90 mg/kg/hour for 2 hours). Pharmacokinetics, safety and tolerability assessments were performed up to 14 days. Results The highest dosage of EA‐230 (continuous infusion of 90 mg/kg/hour for 2 hours) showed more than proportional increases in exposure (Cmax136%; AUC0‐last137%), a large volume of distribution (geometric mean and 95% CI: 13 [3–58] L/kg), a high clearance rate (26 [15–43] L/h/kg), and a short half‐life (0.35 [0.13–1.0] minutes). EA‐230 was well tolerated and no safety concerns were observed. Conclusion These dose‐escalating phase I studies with different administration strategies reveal a pharmacokinetic profile of EA‐230 with a large volume of distribution and a short half‐life. Furthermore, EA‐230 was well tolerated and no safety issues emerged. These results have enabled further clinical development in a phase IIa trial assessing the pharmacodynamics of this compound during systemic inflammation described elsewhere in this issue.

A randomized double‐blind, placebo‐controlled clinical phase IIa trial on safety, immunomodulatory effects and pharmacokinetics of EA‐230 during experimental human endotoxaemia

“…Furthermore, all AEs in the active groups were of mild intensity and regarded unlikely or unrelated to study drug treatment. These results are consistent with earlier human phase I trials focusing on safety of EA‐230 in the absence of systemic inflammation reported elsewhere in this issue and indicate that EA‐230 seems to be safe in dosages up to 90 mg/kg/h. Further safety data with higher dosages and/or longer administration duration would be needed to study a possible exposure‐dependent effect.…”

“…Data on the pharmacokinetic profile of EA‐230 reveal a large volume of distribution, a very rapid systemic clearance and accordingly a short half‐life. A finding of interest is the substantially higher plasma concentrations of EA‐230 compared to the phase I continuous dosing study reported elsewhere in this issue, which was performed and analysed within the same institute, using exactly the same dosing regimens (15, 45 and 90 mg/kg/h for 2‐hours). The elimination rates (β) were, however, comparable to those found in the phase I continuous dosage study.…”

“…Subjects were consecutively assigned to the 15, 45 or 90 mg/kg/h group, based on the order of their appearance on the study drug administration day. Dose regimens were based on the phase I studies using the same dosages without any safety concerns reported elsewhere in this issue . Each dosage group consisted of 12 subjects; within each dosage group subjects were randomly assigned to receive either EA‐230 or placebo ( n = 8 active study drug, n = 4 placebo) making use of a randomization list.…”

“…Hereafter, blood samples were centrifuged at 2000 g for 15 minutes at 4°C and plasma samples were stored at −80°C until analysis. EA‐230 concentrations were determined by a validated liquid chromatography tandem mass spectrometry assay as described elsewhere in this issue . The detection range of the method was 0.5–100 ng/mL with low, medium and high quality control concentrations of 1.5, 10 and 75 ng/mL.…”

“…Following these encouraging preclinical results, we performed phase I studies with different dosing regimens that showed EA‐230 to be well‐tolerated with an excellent safety profile (reported elsewhere in this issue).…”