Veklury® (remdesivir)

Pharmacokinetic Profile

This document is in response to your request for information regarding the pharmacokinetic (PK) profile of Veklury® (remdesivir [RDV]).

This response was developed according to evidence-based medicine and contains data from phase 1 studies and phase 3 clinical studies.

Some data may be outside of the US FDA-approved prescribing information. In providing this data, Gilead Sciences, Inc. is not making any representation as to its clinical relevance or to the use of any Gilead product(s). For information about the approved conditions of use of any Gilead drug product, please consult the FDA-approved prescribing information.

The full indication, important safety information, and boxed warnings are available at:
www.gilead.com/-/media/files/pdfs/medicines/covid-19/veklury/veklury_pi.

Summary

Product Labeling1

The PK properties of RDV and metabolites and multiple dose PK parameters in adults with COVID-19 are summarized below in Table 1 and Table 2, respectively.

Phase 1 PK Data for RDV in Healthy Volunteers2

• The PK properties of RDV have been investigated in phase 1 studies with healthy volunteers.
• RDV is primarily (80%) metabolized via carboxylesterase 1 in the liver.
• The T1/2 of RDV is approximately 1 hour.
• Renal clearance is the major elimination pathway for metabolite GS‑441524; however, a majority of RDV elimination is nonrenal.

PK Data for RDV in Specific Populations

• The PK of RDV and its metabolites were evaluated in participants without COVID-19 who had impaired renal function ranging from mild renal impairment to kidney failure on dialysis in a phase 1 study (GS‑US‑540‑9015). The PK of RDV and its metabolites were also evaluated in participants hospitalized with COVID-19 in the phase 3 REDPINE study who had severely reduced kidney function, including those with end-stage kidney disease on dialysis. RDV plasma exposure was not affected by renal function.3,4
• The PK of RDV and its metabolites were evaluated in healthy participants and those with moderate or severe hepatic impairment. In general, mean exposures of RDV and its metabolites were similar in participants with moderate hepatic impairment and higher in participants with severe hepatic impairment compared to participants with normal hepatic function. The exposure differences in participants with severe hepatic impairment were not associated with safety events and were consistent with the exposure ranges observed in phase 3 trials.5

Product Labeling1

PK

The PK properties of RDV and metabolites are provided in Table 1. The multiple dose PK parameters of RDV and metabolites in adults with COVID-19 are provided in Table 2.

Table 1. PK Properties of RDV and Metabolites (GS-441524 and GS-704277)1

Abbreviation: CES1=carboxylesterase 1.

aRDV administered as a 30-minute IV infusion (Study GS-US-399-5505); range of median observed on Day 1 and Day 5 or 10.

bRange of protein binding for RDV from 2 independent experiments show no evidence of concentration‑dependent protein binding for RDV.

cMedian (Study GS-US-399-4231).

dMean (Study GS-US-399-4231).

Table 2. Multiple Dose PK Parametersa of RDV and Metabolites (GS-441524 and GS‑704277) Following IV Administration of RDV 100 mg to Adults With COVID-191

Abbreviation: Ctrough=observed drug trough concentration.

aPopulation PK estimates for 30-minute IV infusion of RDV for 3 days (Study GS-US-540-9012; n=147).

bGeometric mean estimates.

cNot detectable at 24 hours post-dose

Please refer to the US FDA-approved prescribing information for additional information regarding PK of RDV in and its circulating metabolites (GS-441524 and GS-704277) in specific populations, including pregnant individuals, patients with renal impairment, patients with hepatic impairment, and pediatric patients.

Phase 1 PK Data for RDV in Healthy Volunteers

The PK of RDV have been evaluated in healthy adult volunteers in single-dose and multiple‑dose phase 1 trials.2 The lyophilized and solution formulations of RDV provided similar PK parameters and supported infusion durations of 30 to 120 minutes. The regimen of an RDV 200 mg loading dose followed by once-daily RDV 100 mg maintenance doses was based on results from both in vivo and PK analyses in rhesus monkeys and healthy adult participants.2,6,7

Multiple-Dose Study2

A phase 1, randomized, blinded, placebo-controlled clinical trial was conducted in healthy volunteers who received RDV 200 mg on Day 1 followed by 100 mg via IV infusion daily for either 4 days (Cohort 1; n=10 [RDV, n=8; placebo, n=2]) or 9 days (Cohort 2; n=25 [RDV, n=20; placebo, n=5]). Baseline characteristics were generally balanced between the cohorts. Healthy volunteers had a median (range) age of 31 (20–44) years, 80.6% were male, and 61.1% were White.

The PK of RDV, GS‑704277, and GS-441524 metabolites in plasma and the PK of GS‑443902 in PBMCs were similar at Days 5 (Cohort 1) and 10 (Cohort 2). The median RDV Tmax was approximately 0.7 hours after the start of the 30-minute IV infusion (Table 3). The steady state of GS‑441524 was reached on Day 4, and neither RDV nor GS‑704277 showed evidence of accumulation. High intracellular trough concentrations of the active triphosphate metabolite, GS‑443902, were observed in PBMCs after administration of both single and multiple doses of RDV, which suggested efficient conversion from RDV into the triphosphate form.

Table 3. PK Parameters of RDV and Metabolites After Single and Multiple Doses2

Abbreviations:AUC0–24h=AUC over 24 hours; Cτ=observed drug concentration at the end of the dosing interval; CLss=steady-state clearance; CV=coefficient of variation; Vd=volume of distribution.

an=25.

bAUC0–24h is presented for Day 1 after a single RDV 200 mg dose. AUCτ is presented for Days 5 and 10 after multiple RDV 100 mg doses.

cn=20.

Overall, RDV was generally well tolerated, and no serious AEs, Grade ≥3 AEs, or deaths were reported. The most frequently reported Grade ≤2 AE was infusion-site phlebitis (40%).

PK Data for RDV in Specific Populations

Renal Impairment

The PK of RDV and its metabolites were evaluated in participants without COVID-19 who had impaired renal function ranging from mild renal impairment to kidney failure on dialysis in a phase 1 study (GS‑US‑540‑9015). The PK of RDV and its metabolites were also evaluated in participants hospitalized with COVID-19 in the phase 3 REDPINE study who had severely reduced kidney function, including those with kidney failure on dialysis or ongoing acute kidney injury (SCr increase of 50% in the prior 48 hours and sustained for ≥6 hours).3,4

• RDV plasma exposure was not affected by renal function.4
• Baseline eGFR was highly correlated with increasing exposure of the renally eliminated metabolite, GS-441524; in those with kidney failure (fifth percentile eGFR of 2.54 mL/min/1.73 m2), median GS-441524 AUCτ increased up to 5 fold compared with that observed in participants with normal renal function.3,8 In GS‑US‑540‑9015, PK exposures of RDV were not affected by renal function or timing of RDV administration around dialysis. Exposures of GS-441524 and GS-704277 were up to 7.9-fold and 2.8‑fold higher, respectively, in those with renal impairment compared to those with normal renal function. These changes are not considered to be clinically significant.1
• SBECD PK exposures (AUCτ) increased up to 26 fold in participants with kidney failure compared with that observed in participants with normal renal function.8 In GS‑US‑540‑9015, exposures of SBECD were up to 21-fold higher in those with renal impairment compared to those with normal renal function. These changes are not considered to be clinically significant.1
• No new safety signals were identified with increasing plasma exposures of the predominant metabolite, GS-441524, or the excipient SBECD in REDPINE (RDV, n=163; placebo, n=80).4

Hepatic Impairment

The PK of RDV and its metabolites (GS-704277, GS-441524, and GS-443902) were evaluated in a phase 1, open-label study (GS-US-540-9014) in participants with chronic, stable hepatic impairment and healthy volunteers. The study enrolled participants with moderate (CPT score, 7–9) or severe (CPT score, 10–15) hepatic impairment and healthy volunteers who were matched to participants with hepatic impairment according to age, sex, and BMI. All participants received a single IV dose of 100 mg of RDV, and plasma and PBMC samples were collected for 8 days for PK analyses.5,9

• Mean plasma exposure parameters (AUCinf and Cmax) of RDV and its metabolites in participants with moderate hepatic impairment (n=10) were comparable with those in matched participants with normal hepatic function (n=10).5
• Some mean plasma exposure parameters in participants with severe hepatic impairment (n=6) were increased compared with those in matched participants with normal hepatic function (n=6): the unbound AUCinf and Cmax of RDV in plasma were approximately 2.44‑fold and 1.57-fold higher, respectively; the AUCinf of GS-704277 in plasma was approximately 2.41-fold higher; and the Cmax of GS-441524 in plasma was approximately 1.48-fold higher.5
• GS-443902 AUC and Cmax were comparable in participants with moderate and severe hepatic impairment.9
• The incidences of AEs were similar between participants with hepatic impairment and matched participants with normal hepatic function. All AEs were Grade ≤2.5
• The authors noted that in participants with hepatic impairment, the increased exposure parameters were not associated with the occurrence of safety events, and exposure values were consistent with the exposure ranges observed in phase 3 studies.5

References

1. VEKLURY®, Gilead Sciences Inc. Veklury® (remdesivir) for injection, for intravenous use. U.S. Prescribing Information. Foster City, CA.

2. Humeniuk R, Mathias A, Kirby BJ, et al. Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of Remdesivir, a SARS-CoV-2 Replication Inhibitor. Clin Pharmacokinet. 2021;60(5):569-583.

3. Humeniuk R. Pharmacokinetics Inform Remdesivir Dosing for Patients With Severe Renal Impairment [Poster 514]. Paper presented at: CROI; February 19-22, 2023; Seattle, USA.

4. Sise ME, Santos JR, Goldman JD, et al. Efficacy and Safety of Remdesivir in People With Impaired Kidney Function Hospitalized for COVID-19 Pneumonia: A Randomized Clinical Trial. Clin Infect Dis. 2024;79(5):1172-1181.

5. Regan S, Humeniuk R, Caro L, et al. Pharmacokinetics of SARS-CoV-2 RNA Polymerase Inhibitor Remdesivir in Participants With Moderate and Severe Hepatic Impairment. Clin Transl Sci. 2025;18(2):e70159.

6. Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. 2020.

7. de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2020;117(12):6771-6776.

8. Ramon-Santos J, Goldman JD, Tuttle KR, et al. The REDPINE Study: Efficacy and Safety of Remdesivir in People With Moderately and Severely Reduced Kidney Function Hospitalised for COVID-19 Pneumonia [Poster P2635]. Paper presented at: 33rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID),; April 15-18, 2023; Copenhagen, Denmark.

9. Regan S, Caro L, Chang T, et al. Pharmacokinetics of Remdesivir and Its Metabolites in Participants With Moderate and Severe Hepatic Impairment. Paper presented at: American Society for Clinical Pharmacology & Therapeutics (ASCPT) Annual Meeting; March 22-24, 2023; Atlanta, GA.

Abbreviations

AE=adverse event
AUC=area under the plasma concentration-time curve
AUCinf=area under the plasma concentration-time curve from time 0 to infinity
AUCτ= area under the plasma concentration-time curve over the dosing interval
Cmax=maximum plasma concentration
CPT=Child-Pugh-Turcotte
GS-441524=predominant circulating metabolite of remdesivir
GS-443902=active triphosphate metabolite
GS-704277=intermediate metabolite of remdesivir
PBMC=peripheral blood mononuclear cell
PK=pharmacokinetic(s)
RDV=remdesivir
SBECD=sulfobutylether-β-cyclodextrin sodium salt
T1/2=terminal half-life
Tmax=time to maximum concentration



 

Product Label

For the full indication, important safety information, and boxed warning(s), please refer to the Veklury US Prescribing Information available at:
www.gilead.com/-/media/files/pdfs/medicines/covid-19/veklury/veklury_pi.

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