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

Publication: Pharmacology Research & Perspectives


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 electro-cardiogram (ECG) recordings evaluating its cardiodynamics based on data from singledoses 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 pa-rameters 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 de-scribed 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 maxi-mum 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 concentra-tions enabling adequate target engagement. Results from cardiodynamic assessmentsidentified dose levels and dosing regimens that could be considered for future clinicaltrials, attempting to reduce QT liability.

By Marion Anliker-Ort, Chih-Hsuan Hsin, Andreas Krause, Priska Kaufmann