title: Challenging recommended oral and intravenous voriconazole doses for improved efficacy and safety: population pharmacokinetics-based analysis of adult patients with invasive fungal infections.
abstract: BACKGROUND
  Recommended oral voriconazole (VRC) doses are lower than intravenous doses. Because plasma concentrations impact efficacy and safety of therapy, optimizing individual drug exposure may improve these outcomes.
  
  
  METHODS
  A population pharmacokinetic analysis (NONMEM) was performed on 505 plasma concentration measurements involving 55 patients with invasive mycoses who received recommended VRC doses.
  
  
  RESULTS
  A 1-compartment model with first-order absorption and elimination best fitted the data. VRC clearance was 5.2 L/h, the volume of distribution was 92 L, the absorption rate constant was 1.1 hour(-1), and oral bioavailability was 0.63. Severe cholestasis decreased VRC elimination by 52%. A large interpatient variability was observed on clearance (coefficient of variation [CV], 40%) and bioavailability (CV 84%), and an interoccasion variability was observed on bioavailability (CV, 93%). Lack of response to therapy occurred in 12 of 55 patients (22%), and grade 3 neurotoxicity occurred in 5 of 55 patients (9%). A logistic multivariate regression analysis revealed an independent association between VRC trough concentrations and probability of response or neurotoxicity by identifying a therapeutic range of 1.5 mg/L (>85% probability of response) to 4.5 mg/L (<15% probability of neurotoxicity). Population-based simulations with the recommended 200 mg oral or 300 mg intravenous twice-daily regimens predicted probabilities of 49% and 87%, respectively, for achievement of 1.5 mg/L and of 8% and 37%, respectively, for achievement of 4.5 mg/L. With 300-400 mg twice-daily oral doses and 200-300 mg twice-daily intravenous doses, the predicted probabilities of achieving the lower target concentration were 68%-78% for the oral regimen and 70%-87% for the intravenous regimen, and the predicted probabilities of achieving the upper target concentration were 19%-29% for the oral regimen and 18%-37% for the intravenous regimen.
  
  
  CONCLUSIONS
  Higher oral than intravenous VRC doses, followed by individualized adjustments based on measured plasma concentrations, improve achievement of the therapeutic target that maximizes the probability of therapeutic response and minimizes the probability of neurotoxicity. These findings challenge dose recommendations for VRC.
authors.affiliation: Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland. Andres.Pascual@chuv.ch
authors.forename: Andres
authors.initials: A
authors.lastname: Pascual
authors.forename: Chantal
authors.initials: C
authors.lastname: Csajka
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.forename: Saskia
authors.initials: S
authors.lastname: Bolay
authors.forename: Jacques
authors.initials: J
authors.lastname: Bille
authors.forename: Thierry
authors.initials: T
authors.lastname: Calandra
authors.forename: Oscar
authors.initials: O
authors.lastname: Marchetti
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000188:drug therapy*; D010949:Plasma / Q000737:chemistry; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole