Modeling time‐delayed concentration‐QT effects with ACT‐1014‐6470, a novel oral complement factor 5a receptor 1 (C5a1 receptor) antagonist

Abstract

AbstractThe 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.