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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.

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Scott, Janet T, Sharma, Raman, Meredith, Luke W, Dunning, Jake, Moore, Catrin E, Sahr, Foday, Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192, Goodfellow, Ian and Horby, Peter (2020) '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.'. EBioMedicine, Vol 52, e102601.

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Abstract

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.

Item Type: Article
Subjects: QV Pharmacology > QV 38 Drug action.
WA Public Health > Health Problems of Special Population Groups > WA 395 Health in developing countries
WC Communicable Diseases > Virus Diseases > Viral Hemorrhagic Fevers. Other Virus Diseases > WC 534 Viral hemorrhagic fevers
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1016/j.ebiom.2019.102601
Depositing User: Cathy Waldron
Date Deposited: 24 Jan 2020 09:36
Last Modified: 20 Jul 2020 11:11
URI: https://archive.lstmed.ac.uk/id/eprint/13567

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