Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
Early Clinical Development, Research and Early Clinical Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
Br J Clin Pharmacol. 2024 Dec;90(12):3212-3220. doi: 10.1111/bcp.16205. Epub 2024 Aug 12.
Mitiperstat is a novel, highly potent myeloperoxidase inhibitor being evaluated in patients with cardio-metabolic disease (phase 2). These patients often have impaired renal function, which may affect mitiperstat pharmacokinetics. This study assessed mitiperstat pharmacokinetics, safety and tolerability in participants with severe renal impairment and normal renal function, to inform inclusion of participants with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m in phase 3.
Participants with severe renal impairment (eGFR ≥15 and <30 mL/min/1.73 m) who were not on dialysis (n = 10) and group-matched controls (eGFR ≥90 mL/min/1.73 m; n = 10) received a single mitiperstat 2.5 mg oral tablet. Blood samples were collected at intervals for 2 weeks and urine samples for 24 h post-dose.
Total apparent mitiperstat clearance was 10.83 L/h in the severe renal impairment cohort and 25.62 L/h in the control cohort. The area under the plasma concentration-time curve was 2.37-fold higher (90% confidence interval [CI]: 1.79, 3.12) in the severe renal impairment cohort than in the control cohort, with longer elimination half-life and similar maximum concentration. Non-renal clearance was similar between the cohorts.
Mitiperstat apparent clearance was approximately twofold lower in individuals with severe renal impairment than in those with normal renal function. Lower clearance was driven by reduced renal clearance; non-renal clearance was similar. Mitiperstat was generally well tolerated by participants with severe renal impairment and normal renal function. These findings, together with efficacy and safety/tolerability data from phase 2b, will guide the dosing regimen for phase 3.
Mitiperstat 是一种新型、高活性髓过氧化物酶抑制剂，正在心血管代谢疾病患者（Ⅱ期）中进行评估。这些患者常伴有肾功能损害，可能会影响 mitiperstat 的药代动力学。本研究评估了严重肾功能损害和肾功能正常的参与者中 mitiperstat 的药代动力学、安全性和耐受性，为Ⅲ期研究中纳入估计肾小球滤过率（eGFR）<30ml/min/1.73m2 的患者提供依据。
未接受透析的严重肾功能损害患者（eGFR≥15 且<30ml/min/1.73m2，n=10）和组内匹配的对照组（eGFR≥90ml/min/1.73m2，n=10）接受单次口服 2.5mg mitiperstat 片剂。给药后 2 周内每隔一定时间采集血样，24h 内采集尿样。
严重肾功能损害组的总表观 mitiperstat 清除率为 10.83L/h，对照组为 25.62L/h。严重肾功能损害组的血浆浓度-时间曲线下面积（AUC）比对照组高 2.37 倍（90%置信区间[CI]：1.79，3.12），消除半衰期更长，最大浓度相似。两组的非肾清除率相似。
与肾功能正常者相比，严重肾功能损害者的 mitiperstat 表观清除率约低 2 倍。清除率降低是由肾清除率降低引起的，而非肾清除率相似。严重肾功能损害和肾功能正常的参与者对 mitiperstat 总体耐受性良好。这些发现以及Ⅱb 期的疗效和安全性/耐受性数据，将为Ⅲ期研究指导给药方案。
