Background

TKM-130803 is a specific anti-EBOV therapeutic comprised of two small interfering RNAs (siRNA) siLpol-2 and siVP35-2. The pharmacokinetics (PK) of these siRNAs was defined in Ebola virus disease (EVD) patients, with reference to efficacy (ET) and toxicology thresholds (TT). The relationship between PK and patient survival was explored.

Methods

Pharmacokinetic (PK) and pharmacodynamic (PD) data were available for seven participants with EVD in Sierra Leone who received 0·3 mg/kg of TKM-130803 by intravenous infusion over 2 h daily for up to 7 days. Plasma concentration of siRNA was compared to survival at 14 days. PK data were fitted to two-compartment models then Monte Carlo simulated PK profiles were compared to ET (Cmax 0·04–0·57 ng/mL and mean concentration 1·43 ng/mL), and TT (3000 ng/mL).

Findings

Viral loads (VL) were not significantly different at treatment onset or during treatment (p = 0·1) in subjects who survived or died. siRNA was in quantitative excess of virus genomes throughout treatment, but the 95% percentile exceeded TT. The maximum AUC for which the 95% percentile remained under TT was a continuous infusion of 0·15 mg/kg/day. Plasma concentration of both siRNAs were higher in subjects who died compared to subjects who survived (p<0·025 both siRNAs).

Interpretation

TKM-130803 was circulating in molar excess of circulating virus; a level considered needed for efficacy. Given extremely high viral loads it seems likely that the patients died because they were physiologically beyond the point of no return. Subjects who died exhibited some indication of impaired drug clearance, justifying caution in dosing strategies for such patients. This analysis has given a useful insight into the pharmacokinetics of the siRNA in the disease state and illustrates the value of designing PKPD studies into future clinical trials in epidemic situations.

Funding

This work was supported by the Wellcome Trust of Great Britain (grant number 106491/Z/14/Z and 097997/Z/11/A) and by the EU FP7 project PREPARE (602525). The PHE laboratory was funded by the UK Department for International Development. The funders had no role in trial design, data collection or analysis. The views expressed are those of the authors and not necessarily those of Public Health England, the Department of Health, or the EU.

Trial registration

Pan African Clinical Trials Registry PACTR201501000997429.

中文翻译：

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TKM-130803在塞拉利昂埃博拉病毒病患者中的药代动力学：血浆浓度超过目标水平，最严重的患者体内药物蓄积

背景

TKM-130803是一种特殊的抗EBOV治疗药物，由两个小干扰RNA（siRNA）siLpol-2和siVP35-2组成。参照功效（ET）和毒理学阈值（TT）在埃博拉病毒病（EVD）患者中定义了这些siRNA的药代动力学（PK）。探索了PK与患者生存之间的关系。

方法

塞拉利昂有7名EVD参与者的药代动力学（PK）和药效学（PD）数据，每天2小时通过静脉输注接受0·3 mg / kg TKM-130803，每天最多7天。将血浆siRNA浓度与14天生存时间进行比较。将PK数据拟合到两室模型，然后将Monte Carlo模拟的PK分布图与ET（Cmax 0·04–0·57 ng / mL，平均浓度1·43 ng / mL）和TT（3000 ng / mL）进行比较。

发现

 存活或死亡的受试者在治疗开始时或治疗期间（p = 0·1）的病毒载量（VL）没有显着差异。在整个处理过程中，siRNA的数量远远超过了病毒基因组的数量，但95％的百分位数超过了TT。TT下仍保留95％百分数的最大AUC是连续输注0·15 mg / kg / day。与存活的受试者相比，死亡的受试者中两种siRNA的血浆浓度都较高（两种siRNA的p <0·025）。

解释

TKM-130803以摩尔过量的循环病毒进行循环；被认为是功效所需的水平。鉴于病毒载量极高，患者似乎很可能因生理上无法返回而死亡。死亡的受试者表现出药物清除受损的某些迹象，证明对此类患者的用药策略要谨慎。该分析为疾病状态下siRNA的药代动力学提供了有用的见识，并说明了将PKPD研究设计为流行病未来临床试验的价值。

资金

这项工作得到了英国威康信托基金会（批准号106491 / Z / 14 / Z和097997 / Z / 11 / A）和欧盟FP7项目PREPARE（602525）的支持。PHE实验室由英国国际发展部资助。资助者在试验设计，数据收集或分析中没有作用。所表达的观点是作者的观点，不一定是英国公共卫生，卫生署或欧盟的观点。

试用注册

泛非临床试验注册中心PACTR201501000997429。