Multiple-ascending doses of ACT-1014-6470, an oral complement factor 5a receptor 1 (C5a 1 receptor) antagonist: Tolerability, pharmacokinetics and target engagement.

Autor: Anliker-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., Farine H; Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland., Groenen P; Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland., 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: British journal of clinical pharmacology [Br J Clin Pharmacol] 2023 Jan; Vol. 89 (1), pp. 380-389. Date of Electronic Publication: 2022 Sep 07.
DOI: 10.1111/bcp.15508
Abstrakt: Aims: Targeting the complement factor 5a receptor 1 (C5a 1 receptor) offers potential to treat various autoimmune diseases. The C5a 1 receptor antagonist ACT-1014-6470 was well tolerated in a single-ascending dose study in healthy subjects. This double-blind, randomized, placebo-controlled study aimed to investigate the safety, tolerability, pharmacokinetics (PK) and target engagement of multiple-ascending doses of ACT-1014-6470.
Methods: Per dose level, 10 healthy male and female subjects of nonchildbearing potential (1:1 sex ratio) were enrolled to assess 30, 60 and 120 mg ACT-1014-6470 administered twice daily for 4.5 days under fed conditions. Adverse events, clinical laboratory data, vital signs, electrocardiogram and PK blood samples were collected up to 120 h post last dose and ex vivo stimulated matrix metalloproteinase 9 was quantified as target engagement biomarker. At the 60-mg dose level, PK samples were collected until 8 weeks post last dose.
Results: The total adverse event number was 57 and no treatment-related safety pattern was apparent. At steady state, ACT-1014-6470 reached maximum plasma concentrations after 2-3 h and the half-life estimated up to Day 10 was 115-146 h across dose levels. Exposure parameters increased dose-proportionally, steady state was attained between Day 3-5, and ACT-1014-6470 accumulated 2-fold. At the 60-mg dose level, ACT-1014-6470 was quantifiable until 8 weeks after the last dose. Matrix metalloproteinase 9 release was suppressed to endogenous background concentrations up to the last sampling time point, confirming sustained target engagement of ACT-1014-6470.
Conclusion: The compound was generally safe and well tolerated at all dose levels, warranting further clinical investigations.
(© 2022 British Pharmacological Society.)
Databáze: MEDLINE
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