title: Fluconazole dosing predictions in critically-ill patients receiving prolonged intermittent renal replacement therapy: a Monte Carlo simulation approach.
abstract: Fluconazole is a renally-eliminated antifungal commonly used to treat Candida species infections. In critically-ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic (PK) data are available to guide fluconazole dosing. We used previously-published fluconazole clearance data and PK data of critically-ill patients with acute kidney injury to develop a PK model with the goal of determining a therapeutic dosing regimen for critically-ill patients receiving PIRRT. Monte Carlo simulations were performed to create a virtual cohort of patients receiving different fluconazole dosing regimens. Plasma drug concentration-time profiles were evaluated on the probability of attaining a mean 24-hour area under the drug concentration-time curve to minimum inhibitory concentration ratio (AUC24h : MIC) of 100 during the initial 48 hours of antifungal therapy. At the susceptibility breakpoint of Candida albicans (2 mg/L), 93 - 96% of simulated subjects receiving PIRRT attained the pharmacodynamic target with a fluconazole 800-mg loading dose plus 400 mg twice daily (q12h or pre and post PIRRT) regimen. Monte Carlo simulations of a PK model of PIRRT provided a basis for the development of an informed fluconazole dosing recommendation when PK data was limited. This finding should be validated in the clinical setting.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Gharibian
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Mueller
mesh_terms: D058186:Acute Kidney Injury / Q000628:therapy; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002177:Candidiasis / Q000188:drug therapy; D003198:Computer Simulation; D016638:Critical Illness; D015725:Fluconazole / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D017582:Renal Replacement Therapy; D013997:Time Factors
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole