Pharmacokinetics of itraconazole following oral administration to normal volunteers.
The pharmacokinetics of itraconazole, an orally effective, broad-spectrum, systemic antifungal agent, were evaluated in five healthy male volunteers. Each subject was studied on days 1 and 15 at the following dosages: 100 mg once daily (regimen A), 200 mg once daily (regimen B), and 200 mg twice daily (regimen C). On each study day, itraconazole was administered with a standardized meal. Plasma samples were collected for 72 h postdose, and 24-h urine specimens were obtained. On day 1 of regimen C, plasma samples were collected following the second dose. Samples were assayed for itraconazole by a sensitive, reverse-phase, high-performance liquid chromatography method. Wide intersubject variations in itraconazole concentration in plasma versus time profiles were observed on all study days. Absorption appeared to be slow, with day 1 mean peak itraconazole concentrations in plasma of 110 ng/ml at 2.8 h (regimen A), 272 ng/ml at 3.0 h (regimen B), and 553 ng/ml at 3.4 h (regimen C). Mean peak itraconazole concentrations in plasma on day 15 were 412 ng/ml at 3.0 h (regimen A), 1,070 ng/ml at 4.4 h (regimen B), and 1,980 ng/ml at 6.0 h (regimen C). The steady state was achieved by day 13. Respective elimination half-lives on days 1 and 15 were 15 and 34 h (regimen A), 20.7, and 36.5 h (regimen B), and 25 and 41.7 h (regimen C), respectively. The areas under the plasma concentration versus time curves (0 to infinity) on day 1 were 1,320 (regimen A), 4,160 (regimen B), and 12,600 ng.h/ml (regimen C). With the exception of one patient on day 15 of regimen C, itraconazole was not detected in the urine. All data support dose-dependent pharmacokinetic behavior for itraconazole.
Hardin
T C
TC
Department of Pharmacology, Audie L. Murphy Memorial Veterans' Hospital, University of Texas Health Science Center, San Antonio 78284-7765.
Graybill
J R
JR
Fetchick
R
R
Woestenborghs
R
R
Rinaldi
M G
MG
Kuhn
J G
JG
D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D017964:Itraconazole; D007654:Ketoconazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D012016:Reference Values
D000935:Antifungal Agents; D017964:Itraconazole; D007654:Ketoconazole