Safety, tolerability and pharmacokinetics and pharmacodynamics of HL2351, a novel hybrid fc-fused interleukin-1 receptor antagonist, in healthy subjects: A first-in-human study.
Br J Clin Pharmacol
; 86(2): 372-379, 2020 02.
Article
in En
| MEDLINE
| ID: mdl-31658396
ABSTRACT
AIMS:
We performed a first-in-human study with HL2351, a novel hybrid Fc-fused interleukin (IL)-1 receptor antagonist, to evaluate its tolerability, pharmacokinetics and pharmacodynamics (PD) after a single subcutaneous (SC) administration in healthy subjects.METHODS:
A randomized, double-blind, placebo- and active-controlled, dose-escalation study was conducted. Eligible subjects randomly received a single SC administration of HL2351 (1, 2, 4, 8 and 12 mg/kg) or placebo in a ratio of 82. Subjects in the active-controlled group received a single SC administration of anakinra at 100 mg. Serial blood samples were collected for pharmacokinetics and PD analyses. An ex-vivo activation test was performed to evaluate the PD using peripheral blood mononuclear cells treated with IL-1ß. Anti-HL2351 antibodies were determined at baseline and 29 days postdose. Tolerability was assessed throughout the study.RESULTS:
HL2351 was eliminated more slowly than anakinra (terminal half-life 27.21-45.28 vs 3.97 h). Serum concentrations of HL2351 were increased dose-proportionally. The mean apparent clearance of HL2351 were 0.6, 0.66, 0.75, 0.51, 0.65 L/h at 1, 2, 4, 8 and 12 mg/kg, respectively. The percent inhibition of IL-6 expression varied widely (range 0-92.1%), showing no clear trend or discernible difference between HL2351, anakinra and placebo. HL2351 was well tolerated after a single SC administration.CONCLUSION:
HL2351 was well tolerated and showed linear pharmacokinetic characteristics after a single SC administration at doses up to 12 mg/kg in healthy subjects. HL2351 remained in the body 7-11 times longer than anakinra. HL2351 can be developed as a potential therapeutic alternative to anakinra.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Leukocytes, Mononuclear
/
Interleukin 1 Receptor Antagonist Protein
Type of study:
Clinical_trials
/
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Br J Clin Pharmacol
Year:
2020
Type:
Article