title: Pharmacodynamic activity of amphotericin B deoxycholate is associated with peak plasma concentrations in a neutropenic murine model of invasive pulmonary aspergillosis.
abstract: We conducted a dose fractionation study of neutropenic, corticosteroid-immunosuppressed mice to characterize the pharmacodynamic/pharmacokinetic (PK/PD) parameter most closely associated with amphotericin B (AMB) efficacy in the treatment of invasive pulmonary aspergillosis. Pharmacokinetic parameter estimates were determined by a nonparametric population pharmacokinetic analysis of plasma drug concentrations following single intraperitoneal doses (0.25, 1.0, and 3.0 mg/kg of body weight) of amphotericin B deoxycholate. Three dosage groups (0.5, 0.75, and 1.0 mg/kg) fractionated into three dosing intervals (every 8 h [q8h], q24h, or q72h) were tested to discriminate between the PK/PD parameters (the ratio of maximum concentration of drug in serum [Cmax]/MIC, the ratio of area under the concentration-time curve/MIC, and percentage of time above MIC) most closely associated with AMB efficacy over a range of clinically achievable exposures in humans. The efficacy of each regimen was determined by quantitative PCR and survival. Reductions in pulmonary fungal burden and improvements in survival were maximized at the highest peak plasma concentrations in each of the dosage groups. Reductions in pulmonary fungal burden and increased survival were most closely associated with Cmax/MIC, with maximal activity occurring as the Cmax/MIC approached 2.4. In our model, Cmax/MIC is the PK/PD parameter most closely associated with efficacy in the treatment of invasive pulmonary aspergillosis. These data predict that less frequently administered, higher dosages of AMB would optimize efficacy.
authors.affiliation: The University of Texas at Austin College of Pharmacy, Austin, TX, USA. wiederholdn@uthscsa.edu
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Wiederhold
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Tam
authors.forename: Jingduan
authors.initials: J
authors.lastname: Chi
authors.forename: Randall A
authors.initials: RA
authors.lastname: Prince
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
authors.forename: Russell E
authors.initials: RE
authors.lastname: Lewis
mesh_terms: D000666:Amphotericin B / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D004271:DNA, Fungal / Q000032:analysis; D003840:Deoxycholic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004338:Drug Combinations; D005260:Female; D008168:Lung / Q000382:microbiology; D008172:Lung Diseases, Fungal / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D051379:Mice; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009503:Neutropenia / Q000150:complications*
chemical_list: D000935:Antifungal Agents; D004271:DNA, Fungal; D004338:Drug Combinations; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination