Itraconazole clinical pharmacology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]
CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism
NOTE: The plasma concentrations reported below were measured by high-performance liquid chromatography (HPLC) specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported are approximately 3.3 times higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.)
The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%.
The oral bioavailability of itraconazole is maximal when SPORANOX® (itraconazole) Capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100-mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table below:
fig
Doubling the SPORANOX® dose results in approximately a three-fold increase in the itraconazole plasma concentrations in the dose range of 50 mg to 200 mg.
Values given in the table below represent data from a crossover pharmacokinetics study in which 27 healthy male volunteers each took a single 200-mg dose of SPORANOX® Capsules with or without a full meal:
fig
Absorption of itraconazole under fasted conditions in individuals with relative or absolute achlorhydria, such as patients with AIDS or volunteers taking gastric acid secretion suppressors (e.g., H2 receptor antagonists), was increased when SPORANOX® Capsules were administered with a cola beverage. Eighteen men with AIDS received single 200-mg doses of SPORANOX® Capsules under fasted conditions with 8 ounces of water or 8 ounces of a cola beverage in a crossover design. The absorption of itraconazole was increased when SPORANOX® Capsules were coadministered with a cola beverage, with AUC0–24 and Cmax increasing 75% ± 121% and 95% ± 128%, respectively.
Thirty healthy men received single 200-mg doses of SPORANOX® Capsules under fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3 days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When SPORANOX® Capsules were administered after ranitidine pretreatment, itraconazole was absorbed to a lesser extent than when SPORANOX® Capsules were administered alone, with decreases in AUC0–24 and Cmax of 39% ± 37% and 42% ± 39%, respectively. When SPORANOX® Capsules were administered with cola after ranitidine pretreatment, itraconazole absorption was comparable to that observed when SPORANOX® Capsules were administered alone. (See PRECAUTIONS: Drug Interactions.)
Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. Values given in the table below are data at steady-state from a pharmacokinetics study in which 27 healthy male volunteers took 200-mg SPORANOX® Capsules b.i.d. (with a full meal) for 15 days: fig
The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796 ± 185 liters.
Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3–18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 381 ± 95 mL/minute following intravenous administration. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions for more information.)
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References
Adapted from the FDA Package Insert.