Single-dose pharmacokinetics and tolerance of a cholesteryl sulfate complex of amphotericin B administered to healthy volunteers.
Twenty-three healthy volunteer subjects received a single dose of amphotericin B colloidal dispersion or placebo (4:2) in a double-blind, randomized, dose-escalating design. Doses ranged from 0.25 to 1.5 mg/kg of body weight. The medication was administered via intravenous infusion at a rate of 0.5 mg/kg/h. Plasma amphotericin B concentrations increased with increasing doses, resulting in a linear increase in the amphotericin B area under the curve. Concentrations in plasma decreased rapidly upon discontinuation of the infusion, indicating rapid tissue distribution. A log-linear biexponential elimination phase was observed. A three-compartment open model was used to describe the distribution and elimination of amphotericin B. The mean terminal elimination half-life ranged from 86 h at the 0.25-mg/kg dose level to 244 and 235 h at the 1.0- and 1.5-mg/kg dose levels, respectively. Mean total body clearance ranged from 219 to 284 ml/kg/h. The volume of distribution increased with dose, from 3.37 liter/kg at the 0.25-mg/kg dose to 7.92 liter/kg at the 1.5-mg/kg dose. At the lowest dose level, 0.25 mg/kg, the medication was generally well tolerated. Progressive increases in the dose led to increasing side effects. At the 1.5-mg/kg dose level, 50% of the patients on active medication experienced nausea, vomiting, and chills. Physical examinations, ophthalmologic examinations, and clinical laboratory parameters remained within normal limits compared with those obtained during prestudy examinations.
Sanders
S W
SW
Drug Research Center, University of Utah Medical Center, Salt Lake City 84132.
Buchi
K N
KN
Goddard
M S
MS
Lang
J K
JK
Tolman
K G
KG
D000328:Adult; D000666:Amphotericin B / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002788:Cholesterol Esters / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003102:Colloids; D004311:Double-Blind Method; D004341:Drug Evaluation; D004655:Emulsions; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male
D002788:Cholesterol Esters; D003102:Colloids; D004655:Emulsions; D000666:Amphotericin B; C007045:cholesteryl sulfate