title: Population pharmacokinetics of fluconazole after administration of fosfluconazole and fluconazole in critically ill patients.
abstract: OBJECTIVE
  Fluconazole is an antifungal agent that is commonly used to treat patients with serious systemic fungal infections in intensive care units. Fosfluconazole is a phosphate prodrug of fluconazole, which was developed to reduce the volume of fluid required to administer fluconazole by intravenous injection. The objective of this study was to characterize the pharmacokinetics of the antifungal fluconazole after the intravenous administration of the prodrug fosfluconazole or fluconazole in critically ill patients with serious systemic fungal infections, by population pharmacokinetic analysis using the nonmem software package.
  
  
  METHODS
  Clinical biochemical data including serum fluconazole levels were obtained from 57 patients treated in the intensive care unit along with two naïve pooled patients gleaned from previous reports. The pharmacokinetic model of fluconazole was estimated using a one-compartment model. The probability that the area under the concentration-time curve is higher than 800 μg h/mL was determined by simulation.
  
  
  RESULTS
  It was assumed that all the administered fosfluconazole was converted to fluconazole with an estimated fosfluconazole-fluconazole conversion rate constant of 2·05/h. The significant covariates for clearance for fluconazole (CL) and volume of distribution for fluconazole (Vd) were resulted in creatinine clearance (CLcr) and body weight (BW), respectively, in the final pharmacokinetic model equations: CL (L/h) = 0·799 × [CLcr (mL/min)/92·7](0·685) and Vd (L) = 48·1 × [BW (kg)/65](1·40) , where the interpatient variabilities in CL and Vd and the intrapatient variability were 44·8%, 79·7% and 19·8%, respectively. On the basis of the results of the Monte Carlo simulation, the probabilities of target attainment were 60%, 26% and 11% for 400 mg/day administration as fluconazole equivalent at CLcr values of 40, 70 and 100 mL/min, respectively.
  
  
  CONCLUSIONS
  The present population pharmacokinetic analysis strongly indicates that fosfluconazole (and fluconazole) dosage should be optimized in terms of CLcr in critically ill patients.
authors: Laboratory of Clinical Pharmacokinetics, School of Pharmacy, Nihon University, Chiba, Japan.
authors: T
authors: T
authors: Aoyama
authors: K
authors: K
authors: Hirata
authors: R
authors: R
authors: Hirata
authors: H
authors: H
authors: Yamazaki
authors: Y
authors: Y
authors: Yamamoto
authors: H
authors: H
authors: Hayashi
authors: Y
authors: Y
authors: Matsumoto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003198:Computer Simulation; D003422:Critical Care; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007564:Japan; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D009181:Mycoses / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D010755:Organophosphates / Q000008:administration & dosage / Q000627:therapeutic use*; D011355:Prodrugs / Q000008:administration & dosage / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D010755:Organophosphates; D011355:Prodrugs; C486878:fosfluconazole; D015725:Fluconazole