title: Pharmacokinetics and pharmacodynamics of posaconazole for invasive pulmonary aspergillosis: clinical implications for antifungal therapy.
abstract: BACKGROUND
  Posaconazole is a triazole with anti-Aspergillus activity. However, little is known about the utility of posaconazole as primary therapy for invasive pulmonary aspergillosis.
  
  
  METHODS
  An in vitro model of the human alveolus was used to study the impact of minimum inhibitory concentrations (MIC) on exposure-response relationships. The pharmacokinetic-pharmacodynamic relationships of posaconazole were examined in an inhalational murine model of invasive pulmonary aspergillosis. A mathematical model was fitted to the entire data set. This model was then used to describe the relationship between drug exposure, quantified in terms of the area under the concentration time curve to MIC (AUC:MIC) and the observed antifungal effect.
  
  
  RESULTS
  The posaconazole MIC was an important determinant of exposure-response relationships and accounted for a portion of the observed variance. Murine pharmacokinetics were linear for dosages 1-20 mg/kg/day. There was a dose-dependent decline in serum galactomannan concentrations, with near-maximal suppression following 20 mg/kg/day. The murine pharmacokinetic-pharmacodynamic data were well described by the mathematical model. An AUC:MIC ratio of 167 was associated with half-maximal antifungal effect.
  
  
  CONCLUSIONS
  These results provide the experimental foundation for the selection of candidate posaconazole regimens for the primary treatment of invasive pulmonary aspergillosis in profoundly neutropenic hosts.
authors.affiliation: School of Translational Medicine, The University of Manchester, Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust, Manchester, United Kingdom.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Howard
authors.forename: Jodi M
authors.initials: JM
authors.lastname: Lestner
authors.forename: Andrew
authors.initials: A
authors.lastname: Sharp
authors.forename: Lea
authors.initials: L
authors.lastname: Gregson
authors.forename: Joanne
authors.initials: J
authors.lastname: Goodwin
authors.forename: Joanne
authors.initials: J
authors.lastname: Slater
authors.forename: Jayesh B
authors.initials: JB
authors.lastname: Majithiya
authors.forename: Peter A
authors.initials: PA
authors.lastname: Warn
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy / Q000382:microbiology*; D008297:Male; D051379:Mice; D008962:Models, Theoretical; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole