Antifungal activity and pharmacokinetics of posaconazole (SCH 56592) in treatment and prevention of experimental invasive pulmonary aspergillosis: correlation with galactomannan antigenemia

Abstract

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.

FIG. 1

Comparative rates of survival of persistently neutropenic rabbits in treatment groups receiving POC, ITC, or AMB versus in the UC group. To gauge survival over 12 days (x axis) dosage groups for each antifungal compound were combined (P value determined by Mantel-Haenzsel chi-square test). The response of persistently neutropenic rabbits with primary pulmonary aspergillosis to antifungal therapy was also measured by pulmonary infarct score, total lung weight, and pulmonary tissue concentration of residual organisms (log CFU/per gram) in UC (n = 15); rabbits treated with POC2 (n = 6), POC6 (n = 6), and POC20 (n = 6); rabbits treated with ITC2 (n = 6), ITC6 (n = 6), and ITC20 (n = 5); and rabbits treated with AMB at 1 mg/kg/day (n = 6). Values are given as means ± SEM (∗, P < 0.05; §, P < 0.01; ¶, P < 0.001) in comparison to values for UC using an ANOVA test with Bonferroni's correction for multiple comparisons.

FIG. 2

Expression of galactomannan antigenemia in persistently neutropenic rabbits with pulmonary aspergillosis in the following treatment groups: UC, AMB-treated controls, and rabbits treated with POC (upper panel) or with ITC (lower panel). The differences between the antigen concentration-time curves of UC versus those of rabbits treated with POC6 and POC20 are significant (P = 0.05, ANOVA). Differences between antigen concentration-time curves of UC versus rabbits treated with ITC2, ITC6, and ITC20 are also significant (P < 0.001, ANOVA).

FIG. 3

Expression of galactomannan antigenemia in persistently neutropenic rabbits with pulmonary aspergillosis in the prophylaxis group. Results for UC and rabbits treated with POC or with ITC are shown. The antigen concentration-time curves of rabbits treated with POC2, POC6, and POC20 are significantly different from those of UC (P < 0.001, ANOVA). The antigen concentration-time curve of ITC20-treated rabbits, but not that of ITC2- or ITC6-treated rabbit is significantly different from that of UC (P < 0.05, ANOVA).

FIG. 4

Pulmonary infiltrate scores determined by image analysis of serial ultrafast CT scans of UC, POC-treated rabbits, and ITC-treated rabbits. Pulmonary infiltrates increased during the first 6 days in UC and treated rabbits. The pulmonary infiltrate curve ends on day 6 due to mortality in the UC. Pulmonary infiltrates declined following day 6 in both the POC and ITC treatment groups. The ITC curve ends on day 8 due to mortality.

FIG. 5

Effects of POC, ITC, and AMB on hyphal structures and microbiological CL of A. fumigatus in rabbits with pulmonary aspergillosis. (A to D) Progressive reduction of hyphal elements in a representative section in the lungs from each dosage group. (A) UC; (B) POC2; (C) POC6; (D) POC20; (E) ITC20; (F) AMB at 1 mg/kg.

FIG. 6

Comparative rates of survival of persistently neutropenic rabbits receiving antifungal prophylaxis with POC or ITC versus that of UC. To gauge survival over 12 days (x axis) dosage groups for each antifungal compound were combined (P value determined by Mantel-Haenzsel chi-square test). The response of persistently neutropenic rabbits with primary pulmonary aspergillosis to antifungal therapy was measured by pulmonary infarct score, total lung weight, and pulmonary tissue concentration of residual organisms (log CFU per gram) in UC (n = 10); in rabbits treated with POC2 (n = 6), POC6 (n = 6), and POC20 (n = 6); and in rabbits treated with ITC2 (n = 6), ITC6 (n = 6), and ITC20 (n = 6). Values are given as means ± SEM (∗, P < 0.05; §, P < 0.01; ¶, P < 0.001) in comparison to values for UC using an ANOVA test with Bonferroni's correction for multiple comparisons.

FIG. 7

Concentration profiles of POC (A) and ITC (B) in plasma after multiple dosing over 6 days (treatment) and concentration profiles of POC (C) and ITC (D) in plasma after multiple dosing over 10 days (prophylaxis). ●, 2 mg/kg/day; ■, 6 mg/kg/day; ▵, 20 mg/kg/day.