Safety, Pharmacokinetics, and Dose Recommendations for Nirmatrelvir/Ritonavir in Individuals with Mild to Moderate <scp>COVID</scp> ‐19 and Severe Renal Impairment

Patients with severe renal impairment and COVID-19 are at high risk for severe disease and death. Nirmatrelvir/ritonavir, an antiviral therapy for COVID-19, is eliminated by renal excretion and can accumulate in patients with severe renal impairment. The phase 1 Evaluation of Protease Inhibition for COVID-19 in Patients with Severe Renal Impairment (EPIC-SRI) study evaluated the safety and pharmacokinetics of nirmatrelvir/ritonavir for this population. Fifteen participants (3 not requiring hemodialysis, 12 requiring intermittent hemodialysis) received oral nirmatrelvir/ritonavir 300/100 mg on Day 1, followed by nirmatrelvir/ritonavir 150/100 mg once daily on Days 2-5. No treatment-related adverse events were reported. Geometric mean (coefficient of variation) maximum plasma concentration, plasma trough concentration, and area under the concentration-time curve from 0 to 24 hours for daily dosing of nirmatrelvir for participants from the Intermittent Hemodialysis Cohort were 3280 ng/mL (48%), 2188 ng/mL (81%), and 65,700 ng*h/mL (59%), respectively. Geometric mean (coefficient of variation) nirmatrelvir hemodialysis clearance and fraction removed from the body by hemodialysis were 30.5 mL/min (35%) and 6.9% (138%), respectively. Population pharmacokinetic modeling demonstrated that simulated distributions of nirmatrelvir maximum plasma concentration, minimum trough concentration, and area under the concentration-time curve from 0 to 24 hours for daily dosing at the studied regimen were similar to those for virtual subjects with normal to moderate renal function receiving the approved dose of nirmatrelvir/ritonavir. SARS-CoV-2 RNA levels were substantially reduced across both cohorts. Findings suggest that the studied regimen is well tolerated, achieves and maintains adequate exposure, and is suitable for patients with COVID-19 and severe renal impairment. NCT05487040.