title: Pharmacokinetics of different dosing strategies of oral posaconazole in patients with compromised gastrointestinal function and who are at high risk for invasive fungal infection.
abstract: The aim of this study was to assess different dosing strategies that may result in increased posaconazole bioavailability in patients with compromised gastrointestinal function and at high risk for invasive fungal infections. Patients undergoing chemotherapy and at risk for compromised gastrointestinal function received open-label posaconazole at 200 mg three times daily (TID) on days 1 to 8. Patients were randomized to one of three open-label dosing regimens of posaconazole on days 9 to 15: 200 mg TID, 400 mg twice daily (BID), or 400 mg TID. The plasma concentrations of interest on days 8 and 15 were 500 and 700 ng/ml, respectively; day 2 plasma concentrations of 250 and 350 ng/ml were chosen as levels that might result in steady-state concentrations of >500 and >700 ng/ml, respectively. A total of 75 patients enrolled; 52/75 (69%) completed the study, and 49/75 were included in the pharmacokinetic analyses. Mean plasma concentrations were 230, 346, and 637 ng/ml on days 2, 3, and 8, respectively. The day 15 values were 660, 930, and 671 ng/ml for 200 mg TID, 400 mg BID, and 400 mg TID, respectively. In 12 patients with a day 8 posaconazole concentration of <250 ng/ml, an overall benefit of the higher two doses was not apparent, suggesting that a subset of patients has low steady-state plasma concentrations. A change in dosing regimen on day 9 did not lead to higher exposures in these "poor absorbers" on day 15. Poor absorption may be enhanced with a high-fat meal, a nutritional supplement, or acidification.
authors.affiliation: Department I for Internal Medicine, University Hospital Cologne, ZKS Köln–BMBF 01KN1106, University of Cologne, Cologne, Germany. oliver.cornely@ctuc.de
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Cornely
authors.forename: David
authors.initials: D
authors.lastname: Helfgott
authors.forename: Amelia
authors.initials: A
authors.lastname: Langston
authors.forename: Werner
authors.initials: W
authors.lastname: Heinz
authors.forename: Jörg-Janne
authors.initials: JJ
authors.lastname: Vehreschild
authors.forename: Maria J G T
authors.initials: MJ
authors.lastname: Vehreschild
authors.forename: Gopal
authors.initials: G
authors.lastname: Krishna
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.forename: Susan
authors.initials: S
authors.lastname: Huyck
authors.forename: Michael C
authors.initials: MC
authors.lastname: McCarthy
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D059305:Diet, High-Fat; D019587:Dietary Supplements; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D041981:Gastrointestinal Tract / Q000276:immunology* / Q000473:pathology; D006801:Humans; D016867:Immunocompromised Host; D007408:Intestinal Absorption; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D012306:Risk; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole