title: Posaconazole treatment in hematology patients:  a pilot study of therapeutic drug monitoring.
abstract: BACKGROUND
  Posaconazole is indicated for prophylaxis and salvage therapy of invasive fungal infections. Based on pharmacokinetic-pharmacodynamic data, minimum serum concentrations for each indication have been proposed, for example, for prophylaxis >0.5-0.7 mg/L and for primary therapy >1.0 mg/L. Several drugs and comorbidities have been identified to hinder reaching target concentrations. It is postulated that patients with interacting drugs or comorbidities should be monitored for posaconazole concentrations.
  
  
  METHODS
  Patients aged 18 years and above were included for retrospective analysis if at least 1 serum posaconazole concentration was measured in our hospital between June 2009 and May 2010. Serum posaconazole concentrations were measured using a validated liquid chromatographic method with tandem mass-spectrometric analytical method. Patient characteristics, underlying disease, comedication, comorbidities, and therapeutic drug monitoring (TDM) interventions were collected retrospectively, based on (electronic) medical records.
  
  
  RESULTS
  Seventeen patients were included, from whom 42 samples for posaconazole measurement were collected. In total, 8 patients did not reach adequate posaconazole concentration. Sixty percent of patients using a proton pump inhibitor (PPI) did not reach target concentration with a corresponding median concentration of 0.48 mg/L. PPI usage was shown to significantly increase the risk of attaining below-target serum posaconazole concentration (P = 0.04 for all measurements). Graft-versus-host disease and diarrhea were associated with significant below-target concentrations (P = 0.03 and P < 0.001, respectively, for all measurements). One patient developed a breakthrough pulmonary aspergillosis at low posaconazole concentration (0.37 mg/L). Two patients had high concentrations (>3 mg/L), without adverse events. After TDM intervention, 3 out of 4 patients (75%) reached target concentration by spreading the administration of the dose.
  
  
  CONCLUSIONS
  Below-target posaconazole concentrations were significantly more frequent in PPI users, graft-versus-host disease, and diarrhea. TDM seemed to be a helpful tool to identify low concentrations and to optimize posaconazole treatment.
authors.affiliation: Department of Clinical Pharmacy, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marie-Rose B S
authors.initials: MR
authors.lastname: Crombag
authors.forename: Cynthia
authors.initials: C
authors.lastname: Huisman
authors.forename: Elles M
authors.initials: EM
authors.lastname: Kemper
authors.forename: Roger J M
authors.initials: RJ
authors.lastname: Brüggemann
authors.forename: Yuma A
authors.initials: YA
authors.lastname: Bijleveld
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000097:blood* / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D005500:Follow-Up Studies; D006402:Hematologic Diseases / Q000097:blood / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000097:blood / Q000188:drug therapy; D010865:Pilot Projects; D012189:Retrospective Studies; D016896:Treatment Outcome; D014230:Triazoles / Q000097:blood* / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole