Pharmacokinetics Of Remdesivir Research Articles

Efficacy and Safety of Remdesivir in People With Impaired Kidney Function Hospitalized for COVID-19 Pneumonia: A Randomized Clinical Trial.

Few antiviral therapies have been studied in patients with COVID-19 and kidney impairment. Herein, efficacy, safety, and pharmacokinetics of remdesivir, its metabolites, and sulfobutylether-beta-cyclodextrin excipient were evaluated in hospitalized patients with COVID-19 and severe kidney impairment. In REDPINE, a phase 3, randomized, double-blind, placebo-controlled study, participants aged ≥12 years hospitalized for COVID-19 pneumonia with acute kidney injury (AKI), chronic kidney disease (CKD), or kidney failure were randomized 2:1 to receive intravenous remdesivir (200 mg on Day 1; 100 mg daily up to Day 5) or placebo (enrollment: March 2021-March 2022). The primary efficacy endpoint was the composite of all-cause mortality or invasive mechanical ventilation (IMV) through Day 29. Safety was evaluated through Day 60. Although enrollment concluded early, 243 participants were enrolled and treated (remdesivir, n = 163; placebo, n = 80). At baseline, 90 (37.0%) participants had AKI (remdesivir, 60; placebo, 30), 64 (26.3%) had CKD (remdesivir, 44; placebo, 20), and 89 (36.6%) had kidney failure (remdesivir, 59; placebo, 30); 31 (12.8%) were COVID-19 vaccinated. Composite all-cause mortality or IMV through Day 29 was 29.4% and 32.5% in the remdesivir and placebo group, respectively (P = 0.61). Treatment-emergent adverse events were reported in 80.4% versus 77.5% and serious adverse events in 50.3% versus 50.0% of participants who received remdesivir versus placebo, respectively. Pharmacokinetic plasma exposure to remdesivir was not affected by kidney function. Although underpowered, no significant difference in efficacy was observed between treatment groups. REDPINE demonstrated that remdesivir is safe in those with COVID-19 and severe kidney impairment. (EudraCT number: 2020-005416-22; Clinical Trials.gov number: NCT04745351). EudraCT number: 2020-005416-22; Clinical Trials.gov number: NCT04745351.

Population pharmacokinetics and exposure-clinical outcome relationship of remdesivir major metabolite GS-441524 in patients with moderate and severe COVID-19.

Although remdesivir, a prodrug of nucleoside analog (GS-441524), has demonstrated clinical benefits in coronavirus disease 2019 (COVID-19) treatment, its pharmacokinetics (PKs) in patients with COVID-19 remain poorly understood. Therefore, in this study, the PKs of remdesivir and its major metabolite, GS-441524, were evaluated using a population PK (PopPK) approach to understand the PK aspect and exposure-clinical outcome relationship. The serum concentrations of remdesivir and GS-441524 (102 points in 39 patients) were measured using liquid chromatography-tandem mass spectrometry. All patients received 200 mg remdesivir on the first day, followed by 100 mg on 2-5 days, except for one patient who discontinued remdesivir on day 4. The median (range) age, body surface area, and estimated glomerular filtration rate (eGFR) were 70 (42-85), 1.74 m2 (1.36-2.03), and 68 mL/min/1.73 m2 (33-113), respectively. A compartment model with first-order elimination combined with remdesivir and GS-441524 was used for nonlinear mixed-effects model analysis. Remdesivir was rapidly eliminated after infusion, whereas GS-441524 was eliminated relatively slowly (half-time=17.1h). The estimated apparent clearance (CL) and distribution volume of GS-441524 were 11.0L/h (intersubject variability [ISV]%=43.0%) and 271 L (ISV%=58.1%), respectively. The CL of GS-441524 was significantly related to the eGFR (CL × [eGFR/68]0.745 ). The post hoc area under the curve of GS-441524 was unrelated to the recovery rate or aspartate aminotransferase/alanine aminotransferase elevation. Overall, PopPK analysis showed the rapid elimination of remdesivir in the blood, and GS-441524 accumulation depended on eGFR in patients with COVID-19. However, no relevance of exposure-clinical outcome was not suggestive of the dose adjustment of remdesivir.

652: OXYGENATOR IMPACT ON REMDESIVIR IN EXTRACORPOREAL MEMBRANE OXYGENATION CIRCUITS

Introduction: Extra-corporeal membrane oxygenation (ECMO) is a treatment modality known to alter drug pharmacokinetics (PK). The PK changes can result from drug binding to the oxygenator, alterations in clearance, and drug adsorption or sequestration. Levels of drug absorption by polymers, silicone rubber and other materials have been linked to the drugs’ lipophilicity and the published literature is mostly outdated. Additionally, there is limited data regarding the impact of the oxygenator on drug changes in ECMO circuits in comparison to the other components of the ECMO circuit. The purpose of this study was to determine the impact of the Quadrox-i pediatric and adult oxygenators on the PK of remdesivir (RDV) in contemporary ECMO circuits. Methods: One 1/4-in. and one 3/8-in. closed loop ECMO circuits were prepared using custom tubing with polyvinylchloride and superTygon® (Medtronic Inc., Minneapolis, MN) and a Quadrox-i adult or pediatric oxygenator (Maquet). Additionally, one 1/4-in. and one 3/8-in. closed loop ECMO circuits were assembled without an oxygenator in series. RDV was added to the circuit and levels were obtained pre-and post-oxygenator at the following time intervals; 5 mins, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hrs. RDV was also maintained in a glass vial and samples obtained at the same time periods for control purposes. RDV samples were analyzed by liquid chromatography tandem mass spectrometry. Results: For the 3/8-in. circuit with and without an oxygenator, there was a 60-70% RDV loss during the study period. For the 1/4-in. circuits with an oxygenator, there was a 35-60% RDV loss during the study period. For the 1/4-in. circuits without an oxygenator, there was a 5-20% RDV loss during the study period. Conclusions: There was RDV loss within the circuit during the study period and the RDV loss was more pronounced with the larger 3/8-in circuit when compared with the 1/4-in. circuit. This preliminary data suggests RDV dosing may need to be adjusted for concern of drug loss via the ECMO circuit. Additional single and multiple dose studies are needed to validate these findings.

Interpatient variability in the pharmacokinetics of remdesivir and its main metabolite GS-441524 in treated COVID-19 subjects.

BackgroundRemdesivir is the first antiviral drug against SARS-CoV-2 approved for use in COVID-19 patients.ObjectivesTo study the pharmacokinetic inter-individual variability of remdesivir and its main metabolite GS-441524 in a real-world setting of COVID-19 inpatients and to identify possible associations with different demographic/biochemical variables.MethodsInpatients affected by SARS-CoV-2 infections, undergoing standard-dose remdesivir treatment, were prospectively enrolled. Blood samples were collected on day 4, immediately after (C0) and at 1 h (C1) and 24 h (C24) after infusion. Remdesivir and GS-441524 concentrations were measured using a validated UHPLC-MS/MS method and the AUC0–24 was calculated. At baseline, COVID-19 severity (ICU or no ICU), sex, age, BMI and renal and liver functions were assessed. Transaminases and estimated glomerular filtration rate (e-GFR) were also evaluated during treatment. Linear regression, logistic regression and multiple linear regression tests were used for statistical comparisons of pharmacokinetic parameters and variables.ResultsEighty-five patients were included. The mean (CV%) values of remdesivir were: C0 2091 (99.1%) ng/mL, C1 139.7 (272.4%) ng/mL and AUC0–24 2791 (175.7%) ng·h/mL. The mean (CV%) values of GS-441524 were: C0 90.2 (49.5%) ng/mL, C1 104.9 (46.6%) ng/mL, C24 58.4 (66.9) ng/mL and AUC0–24 1976 (52.6%) ng·h/mL. The multiple regression analysis showed that age (P < 0.05) and e-GFR (P < 0.01) were independent predictors of GS-441524 plasma exposure.ConclusionsOur results showed a high interpatient variability of remdesivir and GS-441524 likely due to both age and renal function in COVID-19 inpatients. Further research is required to understand whether the pharmacokinetics of remdesivir and its metabolites may influence drug-related efficacy or toxic effect.

An open-label, randomized, single intravenous dosing study to investigate the effect of fixed-dose combinations of tenofovir/lamivudine or atazanavir/ritonavir on the pharmacokinetics of remdesivir in Ugandan healthy volunteers (RemTLAR)

BackgroundRemdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir.MethodsThis is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion.DiscussionThis study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir.Trial registrationClinicalTrials.gov NCT04385719. Registered 13 May 2020.

Exploration for the effect of renal function and renal replacement therapy on pharmacokinetics of remdesivir and GS‐441524 in patients with COVID‐19: A limited case series

Remdesivir, an antiviral agent for the treatment of coronavirus disease 2019 (COVID‐19), is metabolized intracellularly, with these metabolites eliminated predominantly in urine. Because of a lack of safety and pharmacokinetic (PK) data, remdesivir is not currently recommended for patients with estimated glomerular filtration rate less than 30 ml/min/1.73 m2 and those on hemodialysis. This study evaluated the PKs of remdesivir and its metabolite, GS‐441524, in patients with COVID‐19 who were and were not receiving renal replacement therapy (RRT). This study enrolled two patients with normal renal function, two with impaired renal function not receiving RRT, two receiving continuous RRT (CRRT), and three undergoing intermittent hemodialysis (IHD). Patients were administered 200 mg remdesivir on the first day, followed by 100 mg/day for 5–10 days. Serial blood samples were collected for PK analysis, and PK parameters were assessed by a noncompartmental method. Systemic exposure to remdesivir was higher in patients with impaired renal function and those receiving CRRT than in patients with normal renal function, but was similar in patients undergoing IHD and those with normal renal function. By contrast, systemic exposure to GS‐441524 was highest in patients undergoing IHD, followed by patients with impaired renal function and those receiving CRRT, and lowest in patients with normal renal function. The PK profiles of remdesivir and GS‐441524 varied according to renal function and RRT. The impact of PK changes of remdesivir and its metabolite on safety and efficacy should be considered when administering remdesivir to patients with COVID‐19 with renal impairment.

Pharmacokinetics of Remdesivir and GS-441524 during PIRRT and Seraph 100 Therapy.

The nucleoside analog remdesivir exhibits in vitro efficacy against severe acute respiratory syndrome coronavirus 2 and may shorten the time to recovery of patients with coronavirus disease 2019 (COVID-19), which resulted in an emergency authorization by the Food and Drug Administration (FDA) for

Compassionate use of remdesivir in children with COVID-19.

Children represent a minority of total COVID-19 cases, but studies have reported severe disease and death in pediatric patients. Remdesivir (RDV) has recently demonstrated promising results in adults with COVID-19, but few data have been reported to date in children.A nationwide multicenter observational study was conducted on children with confirmed SARS-CoV-2 receiving compassionate treatment with RDV in Spain. Eight patients were included in the study, four infants and four older children [median age 5 years old; IQR 4 months–11.6 years old]. Half of them had complex underlying medical conditions, and the rest were mostly infants (3/4). Six out of eight children needed Pediatric Intensive Care Unit Admission. No RDV-related adverse outcomes were observed in our patients. Seven have reached successful clinical outcome, but one patient with serious clinical status died due to complications. However, she received RDV very late after the first COVID-19 symptom.Conclusions: In our cohort, most of the patients achieved successful clinical outcome, without observing adverse events. Clinical trials of RDV therapy for children with COVID-19 are urgently needed, to assess the safety, tolerability, efficacy, and pharmacokinetics of RDV in children, as this could be an effective treatment in severe cases.What is Known:• Remdesivir has not been approved to treat COVID-19 in children under 12 years old, although the drug is currently being prescribed in critically ill children.• Remdesivir has recently demonstrated promising results in adults with COVID-19, but few data have been reported to date in paediatric population.What is New:• We report a multicentre cohort of children with confirmed SARS-CoV-2 and severe COVID-19 disease receiving remdesivir during the first month of the pandemic in Spain.• No remdesivir-related adverse outcomes were observed in most of the cases. Seven patients reached successful clinical outcome, and one died due to complications (bacterial sepsis).Supplementary InformationThe online version contains supplementary material available at 10.1007/s00431-020-03876-1.

Treatment Options for Coronavirus Disease 2019 in Patients With Reduced or Absent Kidney Function.

Coronavirus disease 2019, the disease caused by the severe acute respiratory syndrome coronavirus 2 virus, was first identified in the Hubei Province of China in late 2019. Currently, the only role for therapy is treatment of the disease, as opposed to postexposure prophylaxis, however multiple clinical trials are currently ongoing for both treatment and prophylaxis. Treating coronavirus disease 2019 relies on two components; the first is inhibition of the viral entrance and replication within the body and the second is inhibition of an exacerbated immune response which can be seen in patients with severe disease. Many drugs have shown in vitro antiviral activity; however, clinical trials have not been as promising. This review summarizes the current data for the most commonly used drugs for coronavirus disease 2019 and will cover the unique factors that may affect the dosing of these medications in patients with CKD. While clinical trials are ongoing, most are in patients with normal kidney function. During a pandemic, when patients with CKD are at higher risk of both infection and death, it is imperative to include patients these patients in the clinical trials.