First-in-human study with ACT-1014-6470, a novel oral complement factor 5a receptor 1 (C5aR1) antagonist, supported by pharmacokinetic predictions from animals to patients.

Autor: Ort M; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.; Paediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland., Dingemanse J; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland., Hsin CH; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland., Richard M; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland., Huehn E; Department of Preclinical Drug Metabolism and Pharmacokinetics, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland., Sabattini G; Department of Preclinical Drug Metabolism and Pharmacokinetics, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland., van de Wetering J; PRA Health Sciences, Groningen, The Netherlands., Kornberger R; Parexel International GmbH, Berlin, Germany., van den Anker J; Paediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland., Kaufmann P; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Jazyk: angličtina
Zdroj: Basic & clinical pharmacology & toxicology [Basic Clin Pharmacol Toxicol] 2022 Aug; Vol. 131 (2), pp. 114-128. Date of Electronic Publication: 2022 Jun 08.
DOI: 10.1111/bcpt.13756
Abstrakt: Aberrantly controlled activation of the complement system contributes to inflammatory diseases. Safety, tolerability, and pharmacokinetics of single-ascending doses of ACT-1014-6470, a novel orally available complement factor 5a receptor 1 antagonist, were assessed in a randomized, double-blind, placebo-controlled Phase 1 study. Six ACT-1014-6470 doses (0.5-200 mg) were selected after predictions from a Complex Dedrick plot. In each group, ACT-1014-6470 or matching placebo was administered to six and two healthy male individuals under fed conditions, respectively, including a cross-over part with 10 mg administered also under fasted conditions. Pharmacokinetic blood sampling and safety assessments (adverse events, clinical laboratory, vital signs, 12-lead electrocardiogram, and QT telemetry) were performed. ACT-1014-6470 was absorbed with a time to maximum plasma concentration (t max ) of 3 h across dose levels and eliminated with a terminal half-life of 30-46 h at doses ≥ 2.5 mg. Exposure increased approximately dose proportionally. Under fed compared to fasted conditions, ACT-1014-6470 exposure was 2.2-fold higher and t max delayed by 1.5 h. Pharmacokinetic modelling predicted that twice-daily oral administration is warranted in a subsequent multiple-dose study. No clinically relevant findings were observed in safety assessments. ACT-1014-6470 was well tolerated at all doses and could provide a novel therapy with more patient-friendly administration route compared to biologicals.
(© 2022 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)
Databáze: MEDLINE
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