Pharmacokinetics of oral posaconazole in allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease.
OBJECTIVE
To analyze the pharmacokinetics of posaconazole administered as prophylaxis for invasive fungal infections in recipients of hematopoietic stem cell transplants (HSCTs) who have graft-versus-host disease (GVHD).


METHODS
Pharmacokinetic analysis in a subset of posaconazole-treated patients from a large, multicenter, phase III, randomized, double-blind, double-dummy, parallel-group trial that compared posaconazole with fluconazole.


METHODS
Ninety international medical centers.


METHODS
The subset of patients comprised 246 HSCT recipients for whom pharmacokinetic data were available.


METHODS
All patients received posaconazole 200 mg oral suspension 3 times/day for a maximum of 16 weeks.


RESULTS
Blood samples were collected after dosing on day 2; at weeks 2, 4, 8, and 12; and on the last day of oral treatment. After patients had received posaconazole for at least 7 days (i.e., after achieving steady state), both maximum observed posaconazole concentration (C(max)) and average posaconazole concentration (C(av)) were determined. Five patients developed invasive fungal infections while receiving treatment. Median C(av) and C(max) were 611 and 635 ng/ml, respectively, in these five patients and were 922 and 1360 ng/ml, respectively, in the 241 patients without invasive fungal infection. In patients without invasive fungal infection, posaconazole concentrations were not clinically affected by race, body weight, or age. Median plasma posaconazole concentrations were higher in patients with chronic GVHD than in those with acute GVHD. In 18 patients without invasive fungal infection who experienced diarrhea on the day of sampling, posaconazole concentrations were lower than the concentrations in patients without diarrhea. No relationship was observed between alanine aminotransferase, aspartate aminotransferase, or bilirubin levels and posaconazole concentrations.


CONCLUSIONS
Posaconazole 200 mg 3 times/day resulted in median plasma drug concentrations sufficiently high to prevent invasive fungal infections in HSCT recipients with GVHD, without compromising patient safety. Plasma posaconazole concentrations are generally unaffected by demographic variables, including race, sex, body weight, and age.
Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. gopal.krishna@spcorp.com
Gopal
G
Krishna
Monika
M
Martinho
Pranatharthi
P
Chandrasekar
Andrew J
AJ
Ullmann
Hernando
H
Patino
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001835:Body Weight; D002908:Chronic Disease; D003967:Diarrhea / Q000209:etiology; D004311:Double-Blind Method; D005260:Female; D006086:Graft vs Host Disease / Q000150:complications* / Q000209:etiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000517:prevention & control*; D009894:Opportunistic Infections / Q000517:prevention & control*; D044469:Racial Groups; D012737:Sex Factors; D014184:Transplantation, Homologous / Q000009:adverse effects; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole