Concentration–QTc Relationship from a Single Ascending Dose Study of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for the Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer's Disease

Abstract

This is the cardiodynamic evaluation of a single ascending dose study in healthy participants with the primary objective of assessing the effect of ANAVEX3-71, formerly AF710B, on ECG parameters. Twelve-lead ECGs were obtained at 3 time points within 1 hour prior to dosing to establish a baseline and then serially postdose. Concentration–QTc analysis of plasma concentrations of ANAVEX3-71 and metabolite M8 was conducted. ANAVEX3-71 at the studied doses did not have a clinically relevant effect on heart rate or on the PR and QRS intervals. ANAVEX3-71 alone was retained in the primary model due to small fit differences between models which included the metabolite M8. The estimated population slope of the concentration–QTcF relationship was small and slightly negative: −0.017 ms per µg/L, with a small treatment effect-specific intercept of −0.49 ms. An effect on the placebo-corrected, change-from-baseline QTc exceeding 10 ms can be excluded within the full observed ranges of plasma concentrations of ANAVEX3-71 and M8 up to ∼996 and ∼58 µg/L, respectively. The results from this cardiodynamic evaluation demonstrated that ANAVEX3-71 at single ascending doses of 5-200 mg had no clinically relevant effects on any of the studied ECG parameters.