Pharmacokinetics and pharmacodynamics of itepekimab in healthy adults and patients with asthma: Phase I first-in-human and first-in-patient trials.

Autor: Kosloski MP; Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA., Kalliolias GD; Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA., Xu CR; Sanofi, Bridgewater, New Jersey, USA., Harel S; Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA., Lai CH; Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA., Zheng W; Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA., Davis JD; Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA., Kamal MA; Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA.
Jazyk: angličtina
Zdroj: Clinical and translational science [Clin Transl Sci] 2022 Feb; Vol. 15 (2), pp. 384-395. Date of Electronic Publication: 2021 Sep 29.
DOI: 10.1111/cts.13157
Abstrakt: Itepekimab is a monoclonal antibody that targets interleukin (IL-33) and has been shown to reduce airway inflammation and associated tissue damage in preclinical studies. We assessed the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamic profiles of single-ascending and multiple-ascending doses of itepekimab in two randomized, double-blind, placebo-controlled phase I studies. Healthy adults (N = 40) were randomized to the single-dose study and patients with moderate asthma (N = 23) to the multiple-dose study. Itepekimab was administered intravenously (0.3, 1, 3, or 10 mg/kg infusion) or subcutaneously (150 mg) in the single-dose study and subcutaneously (75 or 150 mg weekly for 4 weeks) in the multiple-dose study. Itepekimab exhibited linear PKs across studies and dose-proportional increases in mean maximum concentration in serum and area under the concentration-time curve following single intravenous or multiple subcutaneous doses. Itepekimab demonstrated mean subcutaneous bioavailability of 59-73% and a long terminal half-life (30.0-31.6 days). IL-33 concentrations in most healthy participants and patients with asthma were undetectable at baseline. Following administration of itepekimab in both studies, total IL-33 concentrations increased and blood eosinophils decreased, both with durable effect. Itepekimab was well-tolerated in both studies with no detection of treatment-emergent anti-drug antibody responses.
(© 2021 Sanofi and Regeneron Pharmaceuticals, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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