First-In-Human Safety, Tolerability, and Pharmacokinetics of PPI-1011, a Synthetic Plasmalogen Precursor

IF 3.1 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Cts-Clinical and Translational Science Pub Date : 2025-03-13 DOI:10.1111/cts.70195
Tara Smith, Kaeli J. Knudsen, Shawn A. Ritchie
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Abstract

PPI-1011 is a synthetic plasmalogen precursor designed to augment plasmalogen levels in patients with Rhizomelic chondrodysplasia punctata (RCDP), an ultra-rare genetic disorder caused by a plasmalogen deficiency that results in significant physical and mental delays. We report here a Phase I, randomized, double-blind, placebo-controlled study that evaluated the safety, tolerability, and pharmacokinetics (PK) of single (10–100 mg/kg) and multiple (75 and 100 mg/kg/day) ascending doses of PPI-1011 in healthy adults. All treatment-emergent adverse events (TEAEs) were mild, monitorable, and resolved without intervention, suggesting no significant safety concerns. The most common TEAEs were gastrointestinal in both the placebo and PPI-1011 groups, suggesting they were likely related to the oil-based nature of the formulation. PK analysis confirmed that both single (25, 50, 75 and 100 mg/kg) and multiple-dose (75 and 100 mg/kg, once daily) administration of PPI-1011 significantly increased serum levels of the target plasmalogen (PlsEtn 16:0/22:6). With a once-daily regimen, PPI-1011 administration resulted in a sustained increase of PlsEtn 16:0/22:6 serum concentrations in healthy participants over a duration of 14 days and beyond.

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PPI-1011是一种合成的质原前体,旨在提高Rhizomelic chondrodysplasia punctata (RCDP)患者的质原水平,RCDP是一种超罕见的遗传性疾病,由质原缺乏引起,会导致严重的身体和智力发育迟缓。我们在此报告一项 I 期随机、双盲、安慰剂对照研究,该研究评估了健康成年人服用单次(10-100 毫克/千克)和多次(75 和 100 毫克/千克/天)递增剂量 PPI-1011 的安全性、耐受性和药代动力学 (PK)。所有治疗突发不良事件(TEAEs)均为轻微、可监测且无需干预即可解决,表明没有重大的安全性问题。在安慰剂组和 PPI-1011 组中,最常见的 TEAE 均为胃肠道反应,这表明它们可能与制剂的油基性质有关。PK 分析证实,单剂量(25、50、75 和 100 毫克/千克)和多剂量(75 和 100 毫克/千克,每天一次)服用 PPI-1011 均能显著提高血清中的目标质原(PlsEtn 16:0/22:6)水平。在每天一次的用药方案中,PPI-1011能在14天及更长的时间内持续提高健康参与者的PlsEtn 16:0/22:6血清浓度。
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来源期刊
Cts-Clinical and Translational Science
Cts-Clinical and Translational Science 医学-医学:研究与实验
CiteScore
6.70
自引率
2.60%
发文量
234
审稿时长
6-12 weeks
期刊介绍: Clinical and Translational Science (CTS), an official journal of the American Society for Clinical Pharmacology and Therapeutics, highlights original translational medicine research that helps bridge laboratory discoveries with the diagnosis and treatment of human disease. Translational medicine is a multi-faceted discipline with a focus on translational therapeutics. In a broad sense, translational medicine bridges across the discovery, development, regulation, and utilization spectrum. Research may appear as Full Articles, Brief Reports, Commentaries, Phase Forwards (clinical trials), Reviews, or Tutorials. CTS also includes invited didactic content that covers the connections between clinical pharmacology and translational medicine. Best-in-class methodologies and best practices are also welcomed as Tutorials. These additional features provide context for research articles and facilitate understanding for a wide array of individuals interested in clinical and translational science. CTS welcomes high quality, scientifically sound, original manuscripts focused on clinical pharmacology and translational science, including animal, in vitro, in silico, and clinical studies supporting the breadth of drug discovery, development, regulation and clinical use of both traditional drugs and innovative modalities.
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