Ebola and HIV are found predominately in the same regions of the world and countries in sub-Saharan Africa are most affected by both diseases. For Ebola, no approved therapies exist. However, new investigational drugs are being evaluated to understand if they are effective against the Ebola virus. Remdesivir is an anti-Ebola investigational drug for the treatment of Ebola. Little is known about how the blood levels of remdesivir relate to how effective it is in patients with HIV taking antiretroviral therapy. This study will explore how commonly utilized ART (tenofovir/lamivudine and atazanavir/ritonavir) affect the drug levels of remdesivir.
The study is designed as an open-label, randomized, fixed sequence, single intravenous dosing study to assess the effects of antiretrovirals on remdesivir pharmacokinetics. The selection of healthy volunteers, as opposed to patients with HIV, avoids the greatest possible extent confounding factors, such as enzyme or transporter activity alteration in inflammatory states, concomitant medications potentially impacting drug disposition and other factors which are commonly present in a population of patients and cannot be easily eliminated. Objectives: Primary objective 1. To assess the safety and tolerability of single intravenous doses of remdesivir in adult healthy volunteers 2. To evaluate the intracellular pharmacokinetics of single dose intravenous remdesivir with or without co-administration of oral fixed-dose combination tenofovir/lamivudine with patients serving as their own controls Secondary objectives 1. To evaluate the difference in plasma and intracellular pharmacokinetics of intravenous remdesivir among healthy volunteers receiving tenofovir/lamivudine versus healthy volunteers receiving tenofovir/lamivudine plus atazanavir/ritonavir tablets. 2. To generate a population pharmacokinetic model to describe inter-individual variability in intracellular pharmacokinetics of remdesivir Exploratory objectives 1\. To describe polymorphic variants of relevant kinases that activate TFV and explore possible consequences on remdesivir PK.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
24
Remdesivir (GS-5734) is a nucleoside analogue with in vitro activity against filoviruses EBOV, SUDV, BDBV and MARV, in addition to arenaviruses and coronaviruses
Infectious Diseases Institute
Kampala, Uganda
Number of adverse events categorised by body system
The number of adverse events will be tabulated by body system. All safety parameters will be listed by cohort, subject and visit/time and summarized by treatment and visit/time. No formal statistical hypotheses of the safety or tolerability are to be tested.
Time frame: 30 days
Percentage of participants with adverse events categorised by body system
The incidence of adverse events will be tabulated by body system. All safety parameters will be listed by cohort, subject and visit/time and summarized by treatment and visit/time. No formal statistical hypotheses of the safety or tolerability are to be tested.
Time frame: 30 days
Peak Concentration (CMax) of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma
maximum plasma and intracellular concentration \[Cmax\] of remdesivir with or without co-administration of antiretroviral drugs.
Time frame: last measurable time-point (24 hours)
Time to maximum concentration (TMax) of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma
Time to maximum concentration of remdesivir in plasma and PBMCs with or without co-administration of antiretroviral therapy
Time frame: last measurable time-point (24 hours)
Terminal elimination half-life of remdesivir in plasma and PBMCs
terminal elimination half life of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma with or without co-administration of antiretroviral therapy.
Time frame: 24 hours
Area under concentration-time curve (AUC) of remdesivir
Area under concentration-time curve of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma with or without co-administration of antiretroviral therapy.
Time frame: last measurable time-point (24 hours)
Geometric mean ratio and 90% confidence intervals of remdesivir CMax with and without antiretroviral therapy.
CMax of remdesivir in plasma and PBMCS will be compared with and without antiretroviral therapy.
Time frame: 24 hours
Geometric mean ratio and 90% confidence intervals of remdesivir TMax with and without antiretroviral therapy.
TMax of remdesivir in plasma and PBMCS will be compared with and without antiretroviral therapy.
Time frame: 24 hours
Geometric mean ratio and 90% confidence intervals of remdesivir terminal elimination half-life with and without antiretroviral therapy.
t 1/2 of remdesivir in plasma and PBMCS will be compared with and without antiretroviral therapy.
Time frame: 24 hours
Geometric mean ratio and 90% confidence intervals of remdesivir area under concentration-time curve, with and without antiretroviral therapy.
AUC (0-t) of remdesivir in plasma and PBMCS will be compared with and without antiretroviral therapy. t is the last measurable time-point
Time frame: 24 hours
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