1. 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
- Author
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Steve A. Ward, Foday Sahr, Peter Horby, Ian Goodfellow, Catrin E. Moore, Janet T Scott, Raman Sharma, Luke W. Meredith, Jake Dunning, and Team, RAPIDE-TKM Trial
- Subjects
0301 basic medicine ,Research paper ,Drug Evaluation, Preclinical ,lcsh:Medicine ,medicine.disease_cause ,Severity of Illness Index ,Disease Outbreaks ,0302 clinical medicine ,RNA, Small Interfering ,lcsh:R5-920 ,TKM ,General Medicine ,Viral Load ,wc_534 ,3. Good health ,Treatment Outcome ,030220 oncology & carcinogenesis ,Ebola ,Drug Monitoring ,lcsh:Medicine (General) ,Viral load ,Algorithms ,medicine.medical_specialty ,Cmax ,wa_395 ,qv_38 ,Antiviral Agents ,General Biochemistry, Genetics and Molecular Biology ,Sierra leone ,Sierra Leone ,03 medical and health sciences ,Tekmira ,Pharmacokinetics ,Internal medicine ,medicine ,Humans ,Computer Simulation ,Dosing ,Ebola virus ,Dose-Response Relationship, Drug ,business.industry ,lcsh:R ,Models, Theoretical ,Hemorrhagic Fever, Ebola ,Clinical trial ,030104 developmental biology ,Pharmacodynamics ,Commentary ,business - Abstract
Background: \ud 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.\ud \ud Methods: \ud 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).\ud \ud Findings: \ud 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
- Published
- 2020