The antifungal efficacy, safety, and pharmacokinetics of
posaconazole (
SCH 56592) (POC) were investigated in treatment and prophylaxis of primary
pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Antifungal
therapy consisted of POC at 2, 6, and 20 mg/kg of
body weight per os;
itraconazole (ITC) at 2, 6, and 20 mg/kg per os; or
amphotericin B (AMB) at 1 mg/kg intravenously. Rabbits treated with POC showed a significant improvement in survival and significant reductions in
pulmonary infarct scores, total lung weights, numbers of pulmonary CFU per gram, numbers of computerized-tomography-monitored pulmonary lesions, and levels of
galactomannan antigenemia. AMB and POC had comparable therapeutic efficacies by all parameters. By comparison, animals treated with ITC had no significant changes in outcome variables in comparison to those of untreated controls (UC). Rabbits receiving prophylactic POC at all dosages showed a significant reduction in
infarct scores, total lung weights, and organism clearance from lung tissue in comparison to results for UC (P < 0.01). There was dosage-dependent microbiological clearance of A. fumigatus from lung tissue in response to POC. Serum
creatinine levels were greater (P < 0.01) in AMB-treated animals than in UC and POC- or ITC-treated rabbits. There was no elevation of serum hepatic
transaminase levels in POC- or ITC-treated rabbits. The pharmacokinetics of POC and ITC in plasma demonstrated dose dependency after multiple dosing. The 2-, 6-, and 20-mg/kg dosages of POC maintained plasma
drug levels above the MICs for the entire 24-h dosing interval. In summary, POC at > or =6 mg/kg/day per os generated sustained concentrations in plasma of > or =1 microg/ml that were as effective in the treatment and prevention of
invasive pulmonary aspergillosis as AMB at 1 mg/kg/day and more effective than
cyclodextrin ITC at > or =6 mg/kg/day per os in persistently neutropenic rabbits.