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

Abstract

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 m 2 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.

Population Pharmacokinetics of Remdesivir and GS-441524 in Hospitalized COVID-19 Patients

“…GS-441524 clearance was found to be dependent on the eGFR, which confirms the observations by Choe et al and Sukeishi et al ( 20 , 21 ). Our simulations show that accumulation as a result of reduced GS-441524 clearance leads to markedly higher GS-441524 concentrations in COVID-19 patients with severely reduced renal function.…”

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

“…The PK of remdesivir in COVID‐19 is poorly understood despite the clinical need for remdesivir. Real‐world clinical studies have evaluated the PK of remdesivir and GS‐441524 in patients with COVID‐19 10–12,15,16 . A few real‐world PK studies on remdesivir, including two PopPK analyses, 11,12 have been reported.…”

“…Real‐world clinical studies have evaluated the PK of remdesivir and GS‐441524 in patients with COVID‐19. 10 , 11 , 12 , 15 , 16 A few real‐world PK studies on remdesivir, including two PopPK analyses, 11 , 12 have been reported. Briefly, these studies characterized the rapid elimination of remdesivir and relatively slow elimination of GS‐441524.…”

Uroliths composed of antiviral compound GS‐441524 in 2 cats undergoing treatment for feline infectious peritonitis

“…Because of the unlicensed status, adequate variables for evaluating drug safety of GS‐441524 have not been established in cats. In human patients, remdesivir and its metabolite GS‐441524 are recommended to be used with caution in patients with impaired renal function 12 . With no previous reports of this complication in cats receiving GS‐441524, it is possible that predisposing factors (including renal dysfunction) may make some cats more likely than others to form these medication‐based uroliths 2‐4 .…”