Concentration-QT modeling demonstrates that the selective mineralocorticoid receptor modulator, balcinrenone...

Balcinrenone (AZD9977) is a selective mineralocorticoid receptor modulator in development in combination with dapagliflozin for treatment of heart failure with impaired kidney function and chronic kidney disease. A prespecified concentration-QT analysis was performed based on data from a phase I single ascending dose study prospectively designed as a thorough QT study substitute. Oral single doses of balcinrenone of 5-800 mg, plus fractionated doses of 800 and 1200 mg, were evaluated in 62 healthy male participants. Time-matched 12-lead digital electrocardiogram and plasma concentrations were measured pre-dose and up to 48 h postdose in the participants. Analysis was performed using a linear mixed-effect model, where baseline-adjusted Fridericia-corrected QT interval (ΔQTcF) was a dependent variable and time-matched balcinrenone concentration an independent variable. The model fit was deemed adequate by evaluation of goodness-of-fit plots, and the slope of the concentration-ΔQTcF relationship was nonsignificant (-0.003 ms/μmol/L; 95% confidence interval [CI]: -0.181, 0.176). The high clinical exposure scenario was defined as the maximum concentration (2.156 μmol/L) following the highest expected therapeutic dose (40 mg once daily) under fed conditions and in presence of a strong cytochrome P450 3A4 inhibitor. Estimated baseline-adjusted and placebo-corrected QTcF interval (ΔΔQTcF) at this concentration was 0.35 ms (90% CI: -1.29, 2.00). Furthermore, the upper 90% ΔΔQTcF CI was estimated to be below the threshold of regulatory concern of 10 ms at all observed concentrations (up to 16.7 μmol/L). Hence, it can be concluded that balcinrenone does not induce QTcF prolongation at the high clinical exposure scenario.