1 Standardized high-fat, high-calorie breakfast was given 30 minutes prior to dosing on the morning of Day 15; standardizedmeals given prior to all other doses.
2 Geometric means ± standard deviation
3 Tmax presented as median (range)
Peak plasma concentrations of itraconazole after administration of a single dose of TOLSURAare reached within 2 to 6 hours following oral administration in either thefasted or fed states. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma duringmultiple dosing of TOLSURA. Steady-state concentrations are generally reached within about 15days, with mean Cmax values of 0.6 mcg/ml and 1.7 mcg/ml after oral administration of 130 mgonce daily and 130 mg twice daily, respectivelyAbsorption
Effect of Food
The effect of food on the steady-state pharmacokinetics of itraconazole following administrationof a 130 mg twice daily dose regimen of TOLSURA (2 x 65 mg) for 14.5 days under fed andfasted conditions was eva luated in 20 healthy volunteers. A high-fat meal with total caloriccontent of 919 calories (526 fat calories, 260 carbohydrate calories and 133 protein calories) wasused in the study. The results are shown in Table 7 below.
Table 7: Pharmacokinetic Parameters of Itraconazole Following Administration ofTOLSURA 130 mg (2 x 65 mg capsules) Given Twice Daily for 14.5 DaysUnder Fed and Fasted Conditions in 20 Healthy Subjects
Parameter Treatment Geometric Mean Fed/Fasted Ratio
(%)
90% Confidence
Interval
Cmax_ss
(mcg/mL)
Fed 1.4 ± 0.6 73.7 69.0, 77.3
Fasted 1.9 ± 0.9
Ctrough,ss
(mcg/mL)
Fed 1.0 ± 0.3 90.0 86.4, 97.0
Fasted 1.1 ± 0.6
AUCtau
(hr*mcg/mL)
Fed 13.4 ± 5.0 78.4 74.5, 81.9
Fasted 17.1 ± 8.0
Median Range
Tmax
(hr)
Fed 4.00 0.5 to 10
Fasted 3.50 0.5 to 5

Distribution
Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the mainbinding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids.
Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in alarge apparent volume in the body (>700 L), suggesting extensive distribution into tissues.
Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two tothree times higher than corresponding concentrations in plasma, and the uptake into keratinoustissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid aremuch lower than in plasma.
Elimination
The terminal half-life of itraconazole following repeated dose administration of TOLSURAranges between 34 to 42 hours under fed conditions.
Metabolism
Itraconazole is extensively metabolized by the liver into a large number of metabolites. In vitrostudies have shown that CYP3A4 is the major enzyme involved in the metabolism ofitraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activitycomparable to itraconazole; trough plasma concentrations of this metabolite are about twicethose of itraconazole.
Excretion
Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) withinone week of an oral solution dose. Renal excretion of itraconazole and the active metabolitehydroxyitraconazole account for less than 1% of an intravenous dose. Based on an oralradiolabeled dose, fecal excretion of uncha