候选抗疟化合物MMV367的首次人体安全性、耐受性、药代动力学及初步食物效应研究。
First-in-human safety, tolerability, pharmacokinetics and pilot food-effect study of the candidate antimalarial compound MMV367.
作者信息
Kuemmerle Andrea, Singh Nand, Gossen Denis, Janin Annick, Sharma Raman, Cahn Anthony, Gibson Rachel A, Menakuru Somasekhara R, Lambourne Erin, Dove Tom, Gamo Francisco-Javier, Sanz Laura, Bestgen Benoit, Chalon Stephan
机构信息
MMV Medicines for Malaria Venture, Geneva, Switzerland.
Quotient Sciences, Nottingham, UK.
出版信息
Br J Clin Pharmacol. 2025 Jun;91(6):1821-1833. doi: 10.1111/bcp.70000.
AIM
To evaluate the safety, tolerability and pharmacokinetics in healthy participants of orally administered MMV367 (GSK3772701), a novel antimalarial interfering with Plasmodium falciparum acyl coenzyme A synthetase 10/11 function.
METHODS
This first-in-human study enrolled 47 healthy male and female participants. Part 1 was a randomised, double-blind, placebo-controlled study in which four sequential fasted cohorts received MMV367 single ascending doses (100, 300, 750 and 1500 mg) or placebo (six active, two placebo per cohort). Part 2 was a randomised, open-label crossover (fed-fasted) pilot food-effect study of MMV367 440 mg (n = 8). In Part 3 MMV367 400 mg was administered once daily for 3 days in a single cohort (six active, two placebo).
RESULTS
Treatment-emergent adverse events (TEAEs) occurred in 36.8% (14/38) of participants receiving MMV367 vs 44.4% (4/9) with placebo. There were two MMV367-related TEAEs, and no serious or severe TEAEs or clinically relevant changes in electrocardiograms, vital signs or laboratory tests. In Part 1 (fasted), maximum plasma concentrations occurred between 2.0 and 5.0 h post dose, with a geometric mean half-life of 16.5-18.4 h. Approximate dose proportionality was demonstrated across the dose range (100-1500 mg). In Part 2, MMV367 relative bioavailability (fed vs fasted) was 161.4% (90% confidence interval 148.3, 175.6) for maximum observed concentration (C), 130.4% (122.2, 139.1) for the area under the curve (AUC) until the last measurable concentration and 132.9% (124.1, 142.3) for AUC extrapolated to infinity. In Part 3, geometric mean day 1:3 exposure ratios (geometric co-efficient of variability) were 1.9 (4.9%) for C and 2.1 (7.7%) for the AUC for the defined interval between doses after once-daily dosing for 3 days.
CONCLUSIONS
MMV367 demonstrated acceptable safety, tolerability and pharmacokinetic profiles supporting further development as an antimalarial drug.
目的
评估口服新型抗疟药MMV367（GSK3772701）在健康受试者中的安全性、耐受性和药代动力学，该药物可干扰恶性疟原虫酰基辅酶A合成酶10/11的功能。
方法
这项首次人体研究招募了47名健康男性和女性受试者。第1部分是一项随机、双盲、安慰剂对照研究，四个连续的空腹队列接受MMV367单次递增剂量（100、300、750和1500毫克）或安慰剂（每个队列6名活性受试者、2名安慰剂受试者）。第2部分是一项MMV367 440毫克的随机、开放标签交叉（进食-空腹）食物效应预试验（n = 8）。在第3部分中，一个队列（6名活性受试者、2名安慰剂受试者）每天服用一次MMV367 400毫克，持续3天。
结果
接受MMV367的受试者中36.8%（14/38）出现治疗中出现的不良事件（TEAE），接受安慰剂的受试者中这一比例为44.4%（4/9）。有两例与MMV367相关的TEAE，没有严重或重度TEAE，心电图、生命体征或实验室检查也没有临床相关变化。在第1部分（空腹）中，最大血浆浓度出现在给药后2.0至5.0小时之间，几何平均半衰期为16.5 - 18.4小时。在整个剂量范围（100 - 1500毫克）内显示出近似的剂量比例关系。在第2部分中，MMV367的相对生物利用度（进食与空腹），最大观察浓度（C）为161.4%（90%置信区间148.3, 175.6），至最后可测量浓度的曲线下面积（AUC）为130.4%（122.2, 139.1），外推至无穷大的AUC为132.9%（124.1, 142.3）。在第3部分中，连续3天每日给药后，定义剂量间隔内的几何平均第1天:第3天暴露比（变异系数几何均值），C为1.9（4.9%），AUC为2.1（7.7%）。
结论
MMV367表现出可接受的安全性、耐受性和药代动力学特征，支持其作为抗疟药物进一步开发。
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