Infliximab Pharmacokinetics, Dosing, and Response in Hospitalized Patients with COVID-19 Pneumonia: A Secondary Analysis of a Multinational Randomized Clinical Trial (ACTIV-1 IM).
Academic Article
Overview
abstract
Infliximab may play an important role in reducing mortality in severe COVID-19, though optimal dosing is unknown. This secondary analysis of the ACTIV-1 IM trial characterized infliximab pharmacokinetics and outcomes in patients hospitalized with severe COVID-19. ACTIV-1 IM included patients admitted with COVID-19 pneumonia who received infliximab in addition to routine care. Infliximab was administered as a single 5-mg/kg intravenous dose. The primary exposure variable was predicted infliximab concentrations over 28 days (AUC0-28). Logistic regression modeling was used to relate AUC0-28 to the primary outcome of 28-day mortality, adjusted for age. The relationship between AUC0-28 and the secondary outcome of time to recovery was evaluated using a Fine-Gray model, adjusted for age, with death as a competing risk. AUC0-28 was higher in patients who did not die versus those who died, with a median (range) of 20,681 mg h/L (8379-60,322) versus 17,392 (9543-43,145), P < .001. A 5000-unit increase in AUC0-28 was associated with decreased mortality (OR 0.62, 95% CI 0.43-0.88, P = .008) and decreased composite safety events (OR 0.57, 95% CI 0.45-0.71, P < .001). Higher AUC0-28 was associated with a greater probability of recovery; an AUC0-28 ≤ 17,400 mg h/L was associated with a 3.45-fold higher (95% CI 2.23-5.34) probability of recovery at Day 28, as was an AUC0-28 >17,400 mg h/L, albeit at a lower rate (1.18-fold higher [95% CI 1.07-1.32]), P < .002 for both. Overall, 113/390 (29.0%) patients did not achieve an optimal predicted infliximab AUC0-28 of at least 17,400 mg h/L, particularly those <100 kg and those with the highest baseline disease severity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04593940.
