Time-varying voriconazole clearance during extracorporeal membrane oxygenation

Invasive aspergillosis causes high mortality in critically ill patients, particularly those with viral pneumonitis receiving extracorporeal membrane oxygenation. Achieving effective voriconazole exposure in this setting is difficult, and existing data on drug concentrations during extracorporeal support are inconsistent. To characterize voriconazole pharmacokinetics in adults receiving extracorporeal membrane oxygenation and evaluate the influence of CYP2C19 genotype on drug exposure. This single-center prospective observational study included adults treated with intravenous voriconazole for suspected or confirmed aspergillosis during extracorporeal support. Serial plasma samples were analyzed using population pharmacokinetic modeling to describe drug disposition and simulate dosing regimens. Thirty-one patients (median age 40 years, mean weight 87 kilograms) provided 131 plasma samples; 61% carried reduced-function CYP2C19 variants. Voriconazole concentrations varied widely, with subtherapeutic levels increasing from 28% on days 1-5 to 47% by days 6-10. A dual-pathway model incorporating an early, rapidly decaying circuit sequestration process followed by a logistic rise in intrinsic clearance from 6.2 to 22.3 liters per h best described the data. Intermediate or poor metabolizers had 36% lower late-phase clearance, though genotype effects were estimated with substantial uncertainty. Simulations indicated that standard dosing achieved therapeutic concentrations in only half of patients at 48 h, declining sharply by day 7. Voriconazole clearance during extracorporeal membrane oxygenation is time-varying, with evidence of early circuit sequestration and later metabolic recovery influenced by CYP2C19 genotype. Early and repeated monitoring is required to maintain effective antifungal exposure. Time-varying clearance should inform dosing of voriconazole and other hepatically metabolized agents during extracorporeal support.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04868188.