The Case for Pharmacokinetic/ Pharmacodynamic Studies During Epidemics of High Consequence Pathogens: Tekmira For Ebola Virus Disease in Sierra Leone - European Medical Journal

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The Case for Pharmacokinetic/ Pharmacodynamic Studies During Epidemics of High Consequence Pathogens: Tekmira For Ebola Virus Disease in Sierra Leone

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Microbiology & Infectious Diseases
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Authors:
*Janet T. Scott,1,2 Raman Sharma,3 Luke W. Meredith,4,5 Jake Dunning,6,7 Catrin E. Moore,7 Foday Sahr,8 Steve Ward,3 Ian Goodfellow,4,5 Peter Horby,7 RAPIDE-TKM trial team7

1. Medical Research Council University of Glasgow Centre for Virus Research, Glasgow, UK
2. National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK
3. Liverpool School of Tropical Medicine, Liverpool, UK
4. Department of Pathology, Division of Virology, University of Cambridge, Cambridge, UK5
5. Department of Public Health, University of Makeni, Makeni, Sierra Leone
6. National Infection Service, Public Health England, London, UK
7. Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK
8. Republic of Sierra Leone Armed Forces, Military Hospital 34, Freetown, Sierra Leone
*Correspondence to [email protected]

Disclosure:

Dr Scott reports personal fees from the Wellcome Trust of Great Britain during the conduct of the study; Dr Horby reports grants from the Wellcome Trust of Great Britain and grants from the European Union (EU) during the conduct of the study; Prof Sahr reports grants from the Wellcome Trust of Great Britain and grants from the EU during the conduct of the study.

Acknowledgements:

Dr Scott, Dr Sharma, and Dr Meredith all contributed equally. The authors would like to acknowledge the contribution of the Port Loko Public Health England (PHE) Laboratory in processing samples, the GOAL Ebola Treatment Unit staff who provided clinical care for the subjects and permitted the trial in their clinical facility. 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 PHE, the Department of Health, or the EU. Trial registration: Pan African Clinical Trials Registry PACTR201501000997429. Details on the RAPIDE- TKM trial can be found in the paper by Scott JT et al., titled ‘Pharmacokinetics of TKM-130803 in Sierra Leonean patients with Ebola virus disease: plasma concentrations exceed target levels, with accumulation in the most severe patients.’

Citation:
EMJ Microbiol Infect Dis. ;1[1]:16-17.
Keywords:
Ebola, epidemic, pharmacokinetics, Tekmira (TKM).

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

INTRODUCTION

Pharmacokinetic/pharmacodynamic (PK/PD) studies during epidemics pose substantial logistical and safety challenges. However, the data generated can be used in drug dose optimisation1 and delineating toxicology thresholds (TT). It is possible to draw conclusions from a relatively small number of subjects. PK can alter substantially in the disease state, making information from patients invaluable. This is particularly true for the haemodynamic destruction caused by Ebola virus disease (EVD), culminating in multiorgan failure.2 For example, isolated PK measurements were used to evaluate favipiravir concentrations in EVD patients, and an embedded PK/PD study of Tekmira (TKM-130803) (Arbutus Biopharma, Warminster, Pennsylvania, USA) in EVD patients yielded sufficient information to develop an in silico model, presented below.3,4

METHODS

TKM-130803 is a specific, anti-EVD therapeutic comprised of two small, interfering RNA (siRNA) siLpol-2 and siVP35-2. During the clinical trial in Sierra Leone in 2015, patients were given an intravenous infusion of 0.3 mg/kg of TKM-130803 over 2 hours daily for up to 7 days.2,4 The trial was discontinued having reached a predefined statistical endpoint, which indicated a low probability of demonstrating overall therapeutic benefit compared to historic controls.2 Plasma concentration of siRNA was compared to survival at 14 days. PK data were fitted to two-compartment models, after which Monte Carlo-simulated PK profiles were compared to efficacy thresholds (Cmax: 0.04–0.57 ng/mL; mean concentration: 1.43 ng/mL), and TT (3,000 ng/mL).

RESULTS

siRNA was in quantitative excess of virus genomes throughout treatment: a level considered needed for efficacy, but the 95th percentile exceeded TT. The maximum area under the curve (AUC) for which the 95th percentile remained under TT was a continuous infusion of 0.15 mg/kg per day. Plasma concentration of both types of siRNA were higher in subjects who died, compared with subjects who survived (p<0.025 for both siRNA).

CONCLUSION

Subjects who died exhibited impaired drug clearance, justifying caution in dosing strategies for such patients. This analysis is the first PK model derived from patients with EVD and indicates that such studies are possible, though challenging. It has given a useful insight into the PK of the siRNA in the disease state and illustrates the value of designing PK/PD studies into future clinical trials in epidemic situations.5

References
Nguyen THT et al. Favipiravir pharmacokinetics in Ebola-infected patients of the JIKI trial reveals concentrations lower than targeted. PLoS Negl Trop Dis. 2017;11(2):18. Malvy D et al. Ebola virus disease. Lancet. 2019;393(10174):936-48. Scott JT et al. Pharmacokinetics of TKM-130803 in Sierra Leonean patients with Ebola virus disease: plasma concentrations exceed target levels, with accumulation in the most severe patients. EBioMedicine. 2020;52:102601. Dunning J, Sahr F, Rojek A, et al. Experimental treatment of ebola virus disease with TKM-130803: a single-arm phase 2 clinical trial. Plos Medicine. 2016;13(4). Rojek A et al. Insights from clinical research completed during the west Africa Ebola virus disease epidemic. Lancet Infect Dis. 2017;17(9):E280-92.

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