Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Pharmacol Res Perspect. 2024 Apr;12(2):e1184. doi: 10.1002/prp2.1184.
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.
米替泊芬是一种髓过氧化物酶抑制剂，目前正处于心力衰竭和射血分数保留或轻度降低、非酒精性脂肪性肝炎和慢性阻塞性肺疾病的临床开发阶段。我们旨在使用浓度-校正 QT（C-QT）模型评估米替泊芬引起 QT 间期延长的风险。一项 1 期研究（NCT02712372）中，健康男性志愿者被随机分为单次口服米替泊芬 5、15、45、135 或 405mg 组（每组 6 人）或匹配的安慰剂组（每组 10 人）。在基线（用药前）和用药后 11 个时间点（最多 48 小时）采集时间匹配的药代动力学和数字心电图数据。C-QT 分析被指定为探索性目标。预先指定的线性混合效应模型使用 Fridericia 公式校正的基线调整后 QT 间期（ΔQTcF）作为因变量，米替泊芬血浆浓度作为自变量。初步探索性分析表明，所有模型假设均成立（对心率无影响；适当使用 QTcF；无滞后；线性浓度-反应关系）。模型预测的米替泊芬 5mg 每日一次治疗时最高预期临床暴露（0.093μmol/L）下的平均基线校正和安慰剂校正ΔΔQTcF 为+0.73ms（90%置信区间[CI]：-1.73，+3.19）。上限 90%CI 低于监管关注的既定阈值。与最高观察到的暴露相比，16 倍的差异足以表明不需要阳性对照。米替泊芬在预期治疗浓度下与 QT 间期延长风险无关。
