Pharmacokinetics and Tolerability of the Novel Myeloperoxidase Inhibitor Mitiperstat in Healthy Japanese and Chinese Volunteers.

IF 2.9 3区 医学 Q2 PHARMACOLOGY & PHARMACY Clinical Drug Investigation Pub Date : 2024-11-04 DOI:10.1007/s40261-024-01402-x
Mikael Sunnåker, Chandrali Bhattacharya, Karin Nelander, Malin Aurell, Maria Heijer, Anna Collén, David Han, Julie Holden, Monika Trebski, Pavlo Garkaviy, Hans Ericsson
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Abstract

Background and objective: Mitiperstat (AZD4831) is a novel irreversible oral myeloperoxidase inhibitor in clinical development for heart failure with preserved ejection fraction, metabolic dysfunction-associated steatohepatitis and chronic obstructive pulmonary disease. This study evaluated the pharmacokinetics, safety and tolerability of multiple ascending doses of mitiperstat in healthy male Japanese and Chinese volunteers.

Methods: Three cohorts of eight Japanese participants were randomized to receive once-daily oral doses of mitiperstat 2.5, 5 or 10 mg or matching placebo for 10 days (six receiving mitiperstat and two receiving placebo, per cohort). One cohort of eight Chinese participants was randomized to receive mitiperstat 5 mg or matching placebo for 10 days (six receiving mitiperstat and two receiving placebo).

Results: Mitiperstat was rapidly absorbed, with a time to maximum plasma concentration of 1-2 h. Exposure was dose proportional over the investigated dose range, as assessed by area under the concentration-time curve and maximum and trough plasma concentrations. Steady state was reached within 10 days, and accumulation was observed, consistent with the observed long elimination half-life of mitiperstat (50.2-57.8 h). Except for a few events of maculopapular rash, mitiperstat up to 5 mg was well tolerated in participants of Japanese or Chinese origin.

Conclusions: The pharmacokinetics of mitiperstat were similar among Japanese and Chinese participants. These characteristics were similar to those in a previous multiple ascending-dose study in healthy primarily white and Black/African American volunteers. Therefore, the pharmacokinetics of mitiperstat do not affect dosing regimens in these different populations.

Trial registration: NCT04232345 (03/01/2020).

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新型髓过氧化物酶抑制剂米替司他在日本和中国健康志愿者中的药代动力学和耐受性研究
背景和目的米替哌司他(AZD4831)是一种新型不可逆口服髓过氧化物酶抑制剂,目前正处于临床开发阶段,可用于治疗射血分数保留型心力衰竭、代谢功能障碍相关性脂肪性肝炎和慢性阻塞性肺病。本研究评估了日本和中国健康男性志愿者服用多个升剂量米替哌司坦的药代动力学、安全性和耐受性:三个队列的八名日本参与者被随机分配接受每日一次口服剂量为 2.5、5 或 10 毫克的米替司特或相应的安慰剂,为期 10 天(每个队列六人接受米替司特,两人接受安慰剂)。一个由8名中国参与者组成的队列随机接受米替哌司坦5毫克或相应安慰剂,为期10天(6人接受米替哌司坦,2人接受安慰剂):米哌司坦吸收迅速,血浆浓度达到最大值的时间为1-2小时。在研究的剂量范围内,米哌司坦的暴露与剂量成正比,浓度-时间曲线下面积以及血浆浓度的最大值和谷值均可评估这一点。米替哌司坦在 10 天内达到稳定状态,并出现蓄积现象,这与观察到的米替哌司坦的长消除半衰期(50.2-57.8 小时)一致。除了少数斑丘疹外,日本或中国血统的参试者对5毫克以下的米替司他耐受性良好:结论:日本人和中国人服用米替司他的药代动力学相似。结论:日本和中国参试者的药代动力学相似,这些特征与之前在主要为白人和黑人/非洲裔美国人的健康志愿者中进行的多次递增剂量研究相似。因此,米替哌司坦的药代动力学不会影响这些不同人群的给药方案:NCT04232345 (03/01/2020).
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来源期刊
CiteScore
5.90
自引率
3.10%
发文量
108
审稿时长
6-12 weeks
期刊介绍: Clinical Drug Investigation provides rapid publication of original research covering all phases of clinical drug development and therapeutic use of drugs. The Journal includes: -Clinical trials, outcomes research, clinical pharmacoeconomic studies and pharmacoepidemiology studies with a strong link to optimum prescribing practice for a drug or group of drugs. -Clinical pharmacodynamic and clinical pharmacokinetic studies with a strong link to clinical practice. -Pharmacodynamic and pharmacokinetic studies in healthy volunteers in which significant implications for clinical prescribing are discussed. -Studies focusing on the application of drug delivery technology in healthcare. -Short communications and case study reports that meet the above criteria will also be considered. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in Clinical Drug Investigation may be accompanied by plain language summaries to assist readers who have some knowledge, but non in-depth expertise in, the area to understand important medical advances.
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