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 COVID-19 treatment, its pharmacokinetics in patients with COVID-19 remain poorly understood. Therefore, in this study, the pharmacokinetics of remdesivir and its major metabolite, GS-441524, were evaluated using a population pharmacokinetic approach to understand the pharmacokinetics 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 m 2 (1.36-2.03), and 68 mL/min/1.73 m 2 (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 = 17.1 h). The estimated apparent clearance (CL) and distribution volume of GS-441524 were 11.0 L/h (inter-subject 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 AST/ALT elevation. Overall, PPK 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.