Time-varying voriconazole clearance during extracorporeal membrane oxygenation

Area of Science:

• Pharmacology
• Critical Care Medicine
• Infectious Diseases

Background:

• Invasive aspergillosis poses a high mortality risk in critically ill patients, especially those on extracorporeal membrane oxygenation (ECMO).
• Optimizing voriconazole exposure in ECMO patients is difficult due to inconsistent drug concentration data during support.
• CYP2C19 genotype is known to influence voriconazole metabolism.

Purpose of the Study:

• To characterize voriconazole pharmacokinetics in adult ECMO patients.
• To evaluate the impact of CYP2C19 genotype on voriconazole exposure in this population.
• To inform optimal dosing strategies for voriconazole in ECMO patients.

Main Methods:

• Prospective observational study of 31 adult ECMO patients receiving intravenous voriconazole.
• Population pharmacokinetic modeling of serial plasma voriconazole concentrations.
• Analysis of CYP2C19 genotype in relation to voriconazole clearance and exposure.

Main Results:

• Voriconazole concentrations varied widely, with subtherapeutic levels increasing over time (28% on days 1-5 to 47% by days 6-10).
• A dual-pathway model described time-varying clearance, including early circuit sequestration and later metabolic recovery.
• Reduced-function CYP2C19 variants were associated with lower late-phase clearance (36%), though with uncertainty.

Conclusions:

• Voriconazole clearance during ECMO is time-varying, affected by circuit interactions and CYP2C19 genotype.
• Standard voriconazole dosing often fails to achieve therapeutic concentrations in ECMO patients.
• Early and frequent therapeutic drug monitoring is essential for effective antifungal treatment in ECMO patients.