A fluconazole population pharmacokinetics study to improve target attainment in critically ill patients

Purpose: Fluconazole is the recommended step-down therapy from echinocandins for fluconazole-susceptible Candida spp in critically ill patients with invasive candidiasis. However, standard fluconazole dosing does not achieve adequate exposure in these patients. We aimed to identify factors impacting fluconazole pharmacokinetic–pharmacodynamic (PKPD) target attainment and provide a dosing regimen ensuring adequate target attainment in critically ill patients. Methods: A population pharmacokinetics study (popPK) was conducted, combining fluconazole concentration data from eight studies. We used multiple imputation to handle missing covariate data, and Monte Carlo simulations to identify a dosing regimen with at least 90% probability of PKPD target attainment (PTA) in every patient. The PKPD target is the 24-hour area under the unbound concentration-time curve over the minimum inhibitory concentration of 100. Results: Data from 177 critically ill patients were included. A two-compartment popPK model with linear elimination described the data best. Continuous renal replacement therapy (CRRT) status, estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation, and total body weight were statistically significant covariates. However, with standard dosing, only CRRT status and total body weight were clinically relevant, as PTA dropped below 90% for all patients on CRRT, and for patients off-CRRT above 60 kg. A weight-based loading dose and flat maintenance doses of 400 mg (off-CRRT) and 800 mg (CRRT) predicted ≥ 90% PTA across the weight range. Conclusion: We have developed a fluconazole dosing regimen, stratified by weight and CRRT status, that may achieve adequate PTA in critically ill patients. External validation is awaited.