Modeling time-delayed concentration-QT effects with ACT-1014-6470, a novel oral complement factor 5a receptor 1 (C5a 1 receptor) antagonist.

Autor: Anliker-Ort M; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.; Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland., Hsin CH; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland., Krause A; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland., Pfister M; Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland., van den Anker J; Pediatric 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., Kaufmann P; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Jazyk: angličtina
Zdroj: Pharmacology research & perspectives [Pharmacol Res Perspect] 2023 Aug; Vol. 11 (4), pp. e01112.
DOI: 10.1002/prp2.1112
Abstrakt: The novel oral complement factor 5a receptor 1 antagonist ACT-1014-6470 was well tolerated in single- and multiple-ascending dose studies, including 24 h Holter electrocardiogram (ECG) recordings evaluating its cardiodynamics based on data from single doses of 30-200 mg and twice-daily (b.i.d.) dosing of 30-120 mg for 4.5 days. By-time point, categorical, and morphological analyses as well as concentration-QT modeling and simulations were performed. No relevant effect of ACT-1014-6470 on ECG parameters was observed in the categorical and morphological analyses. After single-dose administration, the by-time point analysis indicated a delayed dose-dependent increase in placebo-corrected change from baseline in QT interval corrected with Fridericia's formula (ΔΔQTcF) at >6 h postdose. After b.i.d. dosing, ΔΔQTcF remained elevated during the 24-h recording period, suggesting that the effect was not directly related to ACT-1014-6470 plasma concentration. The concentration-QT model described change from baseline in QTcF (ΔQTcF)-time profiles best with a 1-oscillator model of 24 h for circadian rhythm, an effect compartment, and a sigmoidal maximum effect model. Model-predicted ΔΔQTcF was derived for lower doses and less-frequent dosing than assessed clinically. Median and 90% prediction intervals of ΔΔQTcF for once-daily doses of 30 mg and b.i.d. doses of 10 mg did not exceed the regulatory threshold of 10 ms but would achieve ACT-1014-6470 plasma concentrations enabling adequate target engagement. Results from cardiodynamic assessments identified dose levels and dosing regimens that could be considered for future clinical trials, attempting to reduce QT liability.
(© 2023 Idorsia Pharmaceuticals Ltd. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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