Population pharmacokinetics of fluconazole in critically ill patients receiving continuous venovenous hemodiafiltration - using Monte Carlo Simulations to predict doses for specified pharmacodynamic targets

Patel, Kashyap, Roberts, Jason A., Lipman, Jeffrey, Tett, Susan E., Deldot, Megan E. and Kirkpatrick, Carl M. (2011) Population pharmacokinetics of fluconazole in critically ill patients receiving continuous venovenous hemodiafiltration - using Monte Carlo Simulations to predict doses for specified pharmacodynamic targets. Antimicrobial Agents and Chemotherapy, 55 12: 5868-5873. doi:10.1128/AAC.00424-11

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Author Patel, Kashyap
Roberts, Jason A.
Lipman, Jeffrey
Tett, Susan E.
Deldot, Megan E.
Kirkpatrick, Carl M.
Title Population pharmacokinetics of fluconazole in critically ill patients receiving continuous venovenous hemodiafiltration - using Monte Carlo Simulations to predict doses for specified pharmacodynamic targets
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 0066-4804
1098-6596
Publication date 2011-12
Sub-type Article (original research)
DOI 10.1128/AAC.00424-11
Open Access Status File (Publisher version)
Volume 55
Issue 12
Start page 5868
End page 5873
Total pages 6
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Collection year 2012
Language eng
Formatted abstract
Fluconazole is a widely used antifungal agent that is extensively reabsorbed in patients with normal renal function. However, its reabsorption can be compromised in patients with acute kidney injury, thereby leading to altered fluconazole clearance and total systemic exposure. Here, we explore the pharmacokinetics of fluconazole in 10 critically ill anuric patients receiving continuous venovenous hemodiafiltration (CVVHDF). We performed Monte Carlo simulations to optimize dosing to appropriate pharmacodynamic endpoints for this population. Pharmacokinetic profiles of initial and steady-state doses of 200 mg intravenous fluconazole twice daily were obtained from plasma and CVVHDF effluent. Nonlinear mixed-effects modeling (NONMEM) was used for data analysis and to perform Monte Carlo simulations. For each dosing regimen, the free drug area under the concentration-time curve (fAUC)/MIC ratio was calculated. The percentage of patients achieving an AUC/MIC ratio greater than 25 was then compared for a range of MIC values. A two-compartment model adequately described the disposition of fluconazole in plasma. The estimate for total fluconazole clearance was 2.67 liters/h and was notably 2.3 times faster than previously reported in healthy volunteers. Of this, fluconazole clearance by the CVVHDF route (CLCVVHDF) represented 62% of its total systemic clearance. Furthermore, the predicted efficiency of CLCVVHDF decreased to 36.8% when filters were in use >48 h. Monte Carlo simulations demonstrated that a dose of 400 mg twice daily maximizes empirical treatment against fungal organisms with MIC up to 16 mg/liter. This is the first study we are aware of that uses Monte Carlo simulations to inform dosing requirements in patients where tubular reabsorption of fluconazole is probably nonexistent.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Medicine Publications
School of Pharmacy Publications
 
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Created: Mon, 03 Oct 2011, 12:15:30 EST by Charna Kovacevic on behalf of School of Pharmacy