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.
Drug Research Center, University of Utah Medical Center, Salt Lake City 84132.
S W
SW
Sanders
K N
KN
Buchi
M S
MS
Goddard
J K
JK
Lang
K G
KG
Tolman
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