The myeloperoxidase inhibitor mitiperstat (AZD4831) does not prolong the QT interval at expected therapeutic doses

Abstract

Abstract Mitiperstat is a myeloperoxidase inhibitor in clinical development for treatment of patients with heart failure and preserved or mildly reduced ejection fraction, non‐alcoholic steatohepatits and chronic obstructive pulmonary disease. We aimed to assess the risk of QT‐interval prolongation with mitiperstat using concentration–QT (C‐QT) modeling. Healthy male volunteers were randomized to receive single oral doses of mitiperstat 5, 15, 45, 135, or 405 mg (n = 6 per dose) or matching placebo (n = 10) in a phase 1 study (NCT02712372). Time‐matched pharmacokinetic and digital electrocardiogram data were collected at the baseline (pre‐dose) and at 11 time‐points up to 48 h post‐dose. C‐QT analysis was prespecified as an exploratory objective. The prespecified linear mixed effects model used baseline‐adjusted QT interval corrected for the heart rate by Fridericia's formula (ΔQTcF) as a dependent variable and plasma mitiperstat concentration as an independent variable. Initial exploratory analyses indicated that all model assumptions were met (no effect on heart rate; appropriate use of QTcF; no hysteresis; linear concentration–response relationship). Model‐predicted mean baseline‐corrected and placebo‐adjusted ΔΔQTcF was +0.73 ms (90% confidence interval [CI]: −1.73, +3.19) at the highest anticipated clinical exposure (0.093 μmol/L) during treatment with mitiperstat 5 mg once daily. The upper 90% CI was below the established threshold of regulatory concern. The 16‐fold margin to the highest observed exposure was high enough to mean that a positive control was not needed. Mitiperstat is not associated with risk of QT‐interval prolongation at expected therapeutic concentrations.

Keywords

• biopharmaceutics
• drug safety
• heart failure
• modeling and simulation
• QT prolongation