Assessment of the Pharmacokinetics and Safety of Spesolimab, a Humanised Anti-interleukin-36 Receptor Monoclonal Antibody, in Healthy Non-Japanese and Japanese Subjects: Results from Phase I Clinical Studies

Background and Objective The interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective, humanised, IgG1 antibody that targets the interleukin-36 receptor. We aimed to evaluate the pharmacokinetics, safety and tolerability of sin...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Clinical pharmacokinetics Jg. 61; H. 12; S. 1771 - 1787
Hauptverfasser: Joseph, David, Thoma, Christian, Haeufel, Thomas, Li, Xiujiang
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Cham Springer International Publishing 01.12.2022
Springer Nature B.V
Schlagworte:
Antibodies
Cytokines
Dermatitis
Dose-Response Relationship, Drug
Double-Blind Method
Drug dosages
Half-Life
Healthy Volunteers
Humans
Inflammatory diseases
Infusions, Intravenous
Injections, Subcutaneous
Internal Medicine
Laboratories
Medicine
Medicine & Public Health
Monoclonal antibodies
NCT
NCT02525679
NCT02852824
NCT03100903
NCT03123094
NCT03617835
Original
Original Research Article
Pathogenesis
Pharmacokinetics
Pharmacology
Pharmacology/Toxicology
Pharmacotherapy
Plasma
United States > US
ISSN:0312-5963, 1179-1926, 1179-1926
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Background and Objective The interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective, humanised, IgG1 antibody that targets the interleukin-36 receptor. We aimed to evaluate the pharmacokinetics, safety and tolerability of single and multiple doses of spesolimab in healthy non-Japanese and Japanese subjects. Methods Five phase I clinical studies (three placebo-controlled dose-escalation, two open-label) were conducted in healthy volunteers; single or multiple doses of spesolimab were administered by intravenous infusion or subcutaneous injection. Plasma samples were collected to investigate the pharmacokinetics of spesolimab and evaluate changes with respect to dose, frequency of dosing, formulation and injection site. Immunogenicity, safety and tolerability were also assessed. Results Intravenous spesolimab exhibited target-mediated drug disposition at low doses (0.01–0.3 mg/kg) and linear kinetics at doses ≥ 0.3 mg/kg. Steady state was not attained after the fourth weekly dose because of the long half-life (3–5 weeks). Bioavailability of subcutaneous spesolimab increased with increasing dose over the range of 150–600 mg and was higher when administered to the thigh than to the abdomen. The pharmacokinetic profile was consistent between Japanese and non-Japanese subjects. Positive anti-drug antibody responses occurred during the terminal phase of the spesolimab concentration–time profile in 26.7–33.3% and 16.7–37.5% of subjects receiving intravenous and subcutaneous spesolimab, respectively. The impact of anti-drug antibodies on spesolimab pharmacokinetics was low in healthy volunteers, with the impact on spesolimab plasma concentrations only observed in a few subjects at higher titres (≥ 11,400). No serious adverse events were reported; intravenous doses up to 1200 mg were well tolerated in healthy volunteers. Conclusions The pharmacokinetic profile and safety data obtained from these phase I clinical studies have been used to guide spesolimab dosing in clinical studies of patients with interleukin-36-mediated diseases. Clinical Trial Registration For Studies 1–5, NCT02525679, NCT02852824, NCT03100903, NCT03123094, NCT03617835.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:0312-5963
1179-1926
1179-1926
DOI:10.1007/s40262-022-01176-5