Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma.
Itraconazole and amphotericin B were compared by using a newly developed model of invasive pulmonary aspergillosis in rabbits immunosuppressed with methylprednisolone and cyclosporin A (CsA). Both itraconazole at 40 mg/kg (given orally) and amphotericin B at 1 mg/kg (given intravenously) had in vivo antifungal activity in comparison with controls. At these dosages, amphotericin B was more effective than itraconazole in reducing the tissue burden (log10 CFU per gram) of Aspergillus fumigatus (P < 0.05) and the number of pulmonary lesions (P < 0.01). However, there was considerable variation in the near-peak concentrations of itraconazole in plasma (median, 4.15 micrograms/ml; range, < 0.5 to 16.8 micrograms/ml) and a strong inverse correlation between concentrations of itraconazole in plasma and the tissue burden of A. fumigatus. An inhibitory sigmoid maximum-effect model predicted a significant pharmacodynamic relationship (r = 0.87, P < 0.001) between itraconazole concentrations in plasma and antifungal activity as a function of the tissue burden of A. fumigatus. This model demonstrated that levels in plasma of greater than 6 micrograms/ml were associated with a significantly greater antifungal effect. Levels in plasma of less than 6 micrograms/ml were associated with a rapid decline in the antifungal effect. Itraconazole, in comparison with amphotericin B, caused a twofold elevation of CsA levels (P < 0.01) but was less nephrotoxic (P < 0.01). This study of experimental pulmonary aspergillosis demonstrated that amphotericin B at 1 mg/kg/day was more active but more nephrotoxic than itraconazole at 40 mg/kg/day, that itraconazole increased concentrations of CsA in plasma, and that the antifungal activity of itraconazole strongly correlated with concentrations in plasma in an inhibitory sigmoid maximum-effect model. These findings further indicate the importance of monitoring concentrations of itraconazole in plasma as a guide to increasing dosage, improving bioavailability, and optimizing antifungal efficacy in the treatment of invasive pulmonary aspergillosis.
Berenguer
J
J
Infectious Diseases Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Ali
N M
NM
Allende
M C
MC
Lee
J
J
Garrett
K
K
Battaglia
S
S
Piscitelli
S C
SC
Rinaldi
M G
MG
Pizzo
P A
PA
Walsh
T J
TJ
D000666:Amphotericin B / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D001228:Aspergillosis / Q000188:drug therapy*; D016572:Cyclosporine / Q000097:blood*; D004347:Drug Interactions; D005260:Female; D017964:Itraconazole / Q000097:blood / Q000627:therapeutic use* / Q000633:toxicity; D007668:Kidney / Q000187:drug effects; D008172:Lung Diseases, Fungal / Q000188:drug therapy*; D011817:Rabbits
D017964:Itraconazole; D000666:Amphotericin B; D016572:Cyclosporine