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

By: My-Luong Vuong, Omar Elkayal, Ruth Van Daele, Jan-Willem C. Alffenaar, Sophie L. Stocker, Jason A. Roberts, Yves Debaveye, Joost Wauters, Beatrijs Mertens, Jasper M. Boonstra, Indy Sandaradura, Deborah J. E. Marriott, Roger J. Brüggemann, Jeroen A. Schouten, Raoul Bergner, Steven Buijk, Isabel Spriet & Erwin Dreesen

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 often fails to achieve adequate drug exposure in this population.

In this study, we identified key factors influencing fluconazole pharmacokinetic–pharmacodynamic (PKPD) target attainment and developed a dosing regimen to ensure optimal exposure in critically ill patients.

We built a population pharmacokinetic (popPK) model by combining fluconazole concentration data from eight studies. Missing covariate data were handled using multiple imputation, and Monte Carlo simulations were used to determine a dosing regimen achieving at least 90% probability of PKPD target attainment (PTA) in all patients. The PKPD target was defined as a 24-hour area under the unbound concentration–time curve over the minimum inhibitory concentration (fAUC/MIC) of 100.

Ultimately, we developed a fluconazole dosing regimen stratified by body weight and continuous renal replacement therapy (CRRT) status, designed to achieve adequate PTA in critically ill patients. These findings support optimized antifungal dosing strategies that may improve clinical outcomes for patients with invasive candidiasis.

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Key Findings

• A two-compartment popPK model with linear elimination best described fluconazole data from 177 critically ill patients.

• Continuous renal replacement therapy (CRRT) status, estimated glomerular filtration rate (using the CKD-EPI creatinine equation), and total body weight were statistically significant covariates.

• With standard dosing, PTA dropped below 90% for all patients on CRRT and for those off-CRRT weighing above 60 kg.

• A weight-based loading dose followed by flat maintenance doses of 400 mg (off-CRRT) and 800 mg (CRRT) achieved ≥90% PTA across the weight range.

VSC Contribution

“Our research would not have been possible without the computational power of VSC. We conducted 70 population PK analyses across multiply imputed datasets — a task that would have taken weeks on local machines. With VSC’s high-performance computing resources, we completed the work in just a fraction of the time.”

Read the full publication in Springer Nature here

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