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Antimicrobial Agents and Chemotherapy, March 2001, p. 857-869, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.857-869.2001

Antifungal Activity and Pharmacokinetics of Posaconazole (SCH 56592) in Treatment and Prevention of Experimental Invasive Pulmonary Aspergillosis: Correlation with Galactomannan Antigenemia

Ruta Petraitiene,1 Vidmantas Petraitis,1 Andreas H. Groll,1 Tin Sein,1 Stephen Piscitelli,2 Myrna Candelario,1 Aida Field-Ridley,1 Nilo Avila,3 John Bacher,4 and Thomas J. Walsh1,*

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute,1 Pharmacokinetics Research Laboratory, Pharmacy Department,2 and Department of Radiology,3 Warren Grant Magnuson Clinical Center and Surgery Service, Veterinary Resources Program, Office of Research Services,4 National Institutes of Health, Bethesda, Maryland

Received 19 June 2000/Returned for modification 22 October 2000/Accepted 29 December 2000

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 >= 6 mg/kg/day per os generated sustained concentrations in plasma of >= 1 µg/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 >= 6 mg/kg/day per os in persistently neutropenic rabbits.

* Corresponding author. Mailing address: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Building 10, Rm. 13N240, Center Dr., Bethesda, MD 20892. Phone: (301) 402-0023. Fax: (301) 402-0575. E-mail: walsht{at}mail.nih.gov.

Antimicrobial Agents and Chemotherapy, March 2001, p. 857-869, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.857-869.2001


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