title: Evaluation of sulfobutylether-β-cyclodextrin (SBECD) accumulation and voriconazole pharmacokinetics in critically ill patients undergoing continuous renal replacement therapy.
abstract: BACKGROUND
  Intravenous (IV) voriconazole is not recommended in patients with creatinine clearance <50 ml/min to avoid potentially toxic accumulation of sulfobutylether-β-cyclodextrin (SBECD). The purpose of this study was to evaluate the pharmacokinetics of SBECD, voriconazole, and voriconazole N-oxide in critically ill patients undergoing continuous renal replacement therapy (CRRT) and to determine if CRRT removes SBECD sufficiently to allow for the use of IV voriconazole without significant risk of SBECD accumulation.
  
  
  METHODS
  This prospective, open-label pharmacokinetic study enrolled patients >18 years old receiving IV voriconazole for a known or suspected invasive fungal infection while undergoing CRRT. Serial blood and effluent samples were collected on days 1, 3, 5, 7, and every 3 to 5 days thereafter. SBECD, voriconazole, and voriconazole N-oxide plasma and effluent concentrations were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic, pharmacodynamic, and pharmacogenetic analyses were conducted.
  
  
  RESULTS
  Ten patients (mean ± standard deviation (SD)) 53 ± 11 years old, 50% male, 81 ± 14 kg, with Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores of 31.5 ± 3.8 were evaluated. All patients underwent continuous venovenous hemofiltration (CVVH) with a median predilution replacement fluid rate of 36 (interquartile range (IQR) 32 to 37) ml/kg/hr and total ultrafiltration rate of 38 (IQR 34 to 39) ml/kg/hr. Mean ± SD voriconazole and SBECD dosages administered were 8.1 ± 2.1 mg/kg/day and 129 ± 33 mg/kg/day, respectively. Voriconazole plasma trough concentrations were >1 mg/L in all patients with CVVH accounting for only 15% of the total body clearance. CVVH accounted for 86% of the total body clearance of SBECD with the majority of the dose being recovered in the effluent. Minimal increases in dose normalized SBECD area under the concentration-time curve from 0 to 12 hours (AUC0-12) (4,484 ± 4,368 to 4,553 ± 2,880 mg*hr/L; P = 0.97) were observed after study day 1.
  
  
  CONCLUSIONS
  CVVH effectively removed SBECD at a rate similar to the ultrafiltration rate. Voriconazole clearance by CVVH was not clinically significant. Standard dosages of IV voriconazole can be utilized in patients undergoing CVVH without significant risk of SBECD accumulation.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01101386 . Registered 6 April 2010.
authors: Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 12850 E Montview Blvd, Mail Stop C238, Aurora, CO, 80045, USA. ty.kiser@ucdenver.edu.
authors: Tyree H
authors: TH
authors: Kiser
authors: Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 12850 E Montview Blvd, Mail Stop C238, Aurora, CO, 80045, USA. doug.fish@ucdenver.edu.
authors: Douglas N
authors: DN
authors: Fish
authors: Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 12850 E Montview Blvd, Mail Stop C238, Aurora, CO, 80045, USA. christina.aquilante@ucdenver.edu.
authors: Christina L
authors: CL
authors: Aquilante
authors: Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 12850 E Montview Blvd, Mail Stop C238, Aurora, CO, 80045, USA. joseph.rower@ucdenver.edu.
authors: Joseph E
authors: JE
authors: Rower
authors: Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 12850 E Montview Blvd, Mail Stop C238, Aurora, CO, 80045, USA. michael.wempe@ucdenver.edu.
authors: Michael F
authors: MF
authors: Wempe
authors: Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 12850 E Montview Blvd, Mail Stop C238, Aurora, CO, 80045, USA. rob.maclaren@ucdenver.edu.
authors: Robert
authors: R
authors: MacLaren
authors: Department of Medicine, University of Colorado Anschutz Medical Campus, 12605 E 16th Ave, Box F774, Aurora, CO, 80045, USA. isaac.teitelbaum@ucdenver.edu.
authors: Isaac
authors: I
authors: Teitelbaum
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D016638:Critical Illness; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D017582:Renal Replacement Therapy; D013812:Therapeutics / Q000009:adverse effects / Q000379:methods*; D065819:Voriconazole / Q000493:pharmacokinetics*; D047392:beta-Cyclodextrins / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D000935:Antifungal Agents; D047392:beta-Cyclodextrins; C093196:SBE4-beta-cyclodextrin; D065819:Voriconazole
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