In Vivo Pharmacokinetic (PK) and Pharmacodynamic (PD) Comparison of amphotericin B (AmB), Liposomal amphotericin (L-AmB), and ABLC in Various Organs against C. albicans.

D.R. ANDES, N. SAFDAR, K. MARCHILLO, R. CONKLIN

Author address: 

University of Wisconsin, Madison, WI.

Abstract: 

Background: It is generally accepted the lipid formulations of AmB are less potent than conventional AmB. We examined the in vivo potency of these compounds against C. albicans in several organs in a murine model. We subsequently examined the relationship between in vivo efficacy and the PK of the drugs in serum and at the sites of infection. Methods: Neutropenic murine model of disseminated candidiasis and pneumonia were used. The AmB drugs were administered once daily over a 72 h period. Drug doses ranged 256-fold. At the end of therapy CFU were quantified in kidney, liver, spleen, and lung. Data were analyzed using an Emax model. ANOVA was used to compare the ED25, ED50, ED75, and dose to 1 log kill. Drug pharmacokinetics in serum, liver, kidney, and lung were determined over a 4-fold dose range. Differences in potency were examined relative to drug PK. Results: AmB was more potent than each of the lipid preparations at each of the end points and in each end organ. The difference in AmB in vivo potency was similarly prominent in the liver, kidney, and spleen and least evident in the lung. AmB concentrations were higher than the lipid concentrations in the liver and kidney. We were unable to accurately measure concentrations in the spleen. Serum L-AmB concentrations were much higher than the other drugs. ABLC concentrations were highest in the lung and correlated with enhanced potency at this site. Dose (95% CI) AmB Kidney Liver Spleen Lung ED25 0.34 0.29 0.43 0.04 (0.14-0.54) (0.28-0.30) (0.36-1.13) (0.02-0.05) ED50 1.49 0.32 0.78 0.30 (0.58-2.4) (0.31-0.33) (0.43-1.13) (0.20-0.40) ED75 6.30 0.39 1.72 2.27 (2.45-10.1) (0.38-0.40) (0.96-2.48) (2.18-2.36) ED 1 log kill 5.06 0.34 7.13 0.41 (3.28-6.84) (0.33-0.35) (3.96-10.3) (0.27-0.55) Dose (95% CI) AmBisome Kidney Liver Spleen Lung ED25 2.05 0.46 0.41 0.30 (1.85-2.35) (0.29-0.63) (-2.6-2.7) (0.06-0.54) ED50 3.94 1.31 2.98 1.08 (3.37-4.51) (0.82-1.80) (-16.2-22.6) (0.28-1.94) ED75 7.59 3.78 21.7 3.93 (6.59-8.59) (2.38-5.18) (2.1-41.3) (3.06-4.80) ED 1 log kill 11.4 4.17 51.9 1.48 (10.8-12.0) (2.61-5.73) (32.3-71.5) (1.28-1.68) Dose (95% CI) ABLC Kidney Liver Spleen Lung ED25 2.42 1.28 1.36 0.27 (2.08-2.76) (1.08-1.48) (1.23-1.49) (0.26-0.28) ED50 4.11 4.10 2.68 0.47 (3.53-4.69) (3.45-4.75) (2.43-2.93) (0.45-0.49) ED75 7.00 13.1 5.28 0.83 (6.0-8.0) (11.1-15.1) (5.23-5.53) (0.81-0.85) ED 1 log kill 14.8 10.1 7.35 0.57 (12.7-16.9) (8.5-11.7) (6.69-8.01) (0.54-0.60) Conclusion: AmB was more potent in vivo than either of the lipid AmB drugs. ABLC was most potent in the lung. The differences in potency appeared to correlate with differences in kinetics at the infection sites.
2003

abstract No: 

A-1579

Full conference title: 

43rd Interscience Conference on Antimicrobial Agents
    • ICAAC 43rd