[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]
EBioMedicine. 2020 Jan 13:102601. doi: 10.1016/j.ebiom.2019.102601. [Epub ahead of print]
Pharmacokinetics of TKM-130803 in Sierra Leonean patients with Ebola virus disease: plasma concentrations exceed target levels, with drug accumulation in the most severe patients.
Scott JT1, Sharma R2, Meredith LW3, Dunning J4, Moore CE5, Sahr F6, Ward S2, Goodfellow I3, Horby P5; RAPIDE-TKM trial team5.
Author information: 1 MRC-University of Glasgow Centre for Virus Research, G61 1QH, UK; NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK. Electronic address: firstname.lastname@example.org. 2 Liverpool School of Tropical Medicine, Liverpool, UK. 3 Department of Pathology, Division of Virology, University of Cambridge, Cambridge CB2 1QP, UK; Department of Public Health, University of Makeni, Makeni, Sierra Leone. 4 National Infection Service, Public Health England, London, UK; Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK. 5 Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK. 6 Republic Sierra Leone Armed Forces, Military Hosp 34, Freetown, Sierra Leone.
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.
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).
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).
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.
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.
Pan African Clinical Trials Registry PACTR201501000997429.
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
KEYWORDS: Ebola; Pharmacokinetics; TKM; Tekmira
PMID: 31953031 DOI: 10.1016/j.ebiom.2019.102601
Keywords: Antivirals; Ebola; Sierra Leone.