title: Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease.
abstract: BACKGROUND
  Antifungal prophylaxis with a new oral tablet formulation of posaconazole may be beneficial to patients at high risk for invasive fungal disease. A two-part (Phase 1B/3) study evaluated posaconazole tablet pharmacokinetics (PK) and safety.
  
  
  METHODS
  Patients with neutropenia following chemotherapy for haematological malignancy or recipients of allogeneic HSCT receiving prophylaxis or treatment for graft-versus-host disease received 300 mg posaconazole (as tablets) once daily (twice daily on day 1) for up to 28 days without regard to food intake. Weekly trough PK sampling was performed during therapy, and a subset of patients had sampling on days 1 and 8. Cmin-evaluable subjects received ≥6 days of dosing, and were compliant with specified sampling timepoints. Steady-state PK parameters, safety, clinical failure and survival to day 65 were assessed. ClinicalTrials.gov, NCT01777763; EU Clinical Trials Register, EUDRA-CT 2008-006684-36.
  
  
  RESULTS
  Two hundred and ten patients received 300 mg posaconazole (as tablets) once daily. Among Cmin-evaluable subjects (n = 186), steady-state mean Cmin was 1720 ng/mL (range = 210-9140). Steady-state Cmin was ≥700 ng/mL in 90% of subjects with 5% (10 of 186) <500 ng/mL and 5% (10 of 186) 500-700 ng/mL. Six (3%) patients had steady-state Cmin ≥3750 ng/mL. One patient (<1%) had an invasive fungal infection. The most common treatment-related adverse events were nausea (11%) and diarrhoea (8%). There was no increase in adverse event frequency with higher posaconazole exposure.
  
  
  CONCLUSIONS
  In patients at high risk for invasive fungal disease, 300 mg posaconazole (as tablets) once daily was well tolerated and demonstrated a safety profile similar to that reported for posaconazole oral suspension: most patients (99%) achieved steady-state pCavg exposures >500 ng/mL and only one patient (<1%) had a pCavg <500 ng/mL.
authors.affiliation: Department I of Internal Medicine, ZKS Köln, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany oliver.cornely@uk-koeln.de.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Cornely
authors.affiliation: Department of Haematology, Catalan Institute of Oncology, Barcelona, Spain.
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Duarte
authors.affiliation: Juravinski Hospital, Hamilton, Ontario, Canada.
authors.forename: Shariq
authors.initials: S
authors.lastname: Haider
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.
authors.forename: Pranatharthi
authors.initials: P
authors.lastname: Chandrasekar
authors.affiliation: Weill Cornell Medical College, New York, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Helfgott
authors.affiliation: Hospital Ramon y Cajal, Madrid, Spain.
authors.forename: Javier López
authors.initials: JL
authors.lastname: Jiménez
authors.affiliation: University of Udine, Udine, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Candoni
authors.affiliation: Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Issam
authors.initials: I
authors.lastname: Raad
authors.affiliation: Hopital Maisonneuve-Rosemont, Montreal, Quebec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Laverdiere
authors.affiliation: Emory University, Atlanta, GA, USA.
authors.forename: Amelia
authors.initials: A
authors.lastname: Langston
authors.affiliation: MSD, North Wales, PA, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kartsonis
authors.affiliation: MSD, Oss, Netherlands.
authors.forename: Marlou
authors.initials: M
authors.lastname: Van Iersel
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Connelly
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Hetty
authors.initials: H
authors.lastname: Waskin
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018890:Chemoprevention / Q000009:adverse effects / Q000379:methods*; D005260:Female; D016469:Fungemia / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000150:complications; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D016019:Survival Analysis; D013607:Tablets / Q000008:administration & dosage* / Q000009:adverse effects; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D013607:Tablets; D014230:Triazoles; C101425:posaconazole