Food Interaction and Steady‐State Pharmacokinetics of Itraconazole Oral Solution in Healthy Volunteers

STUDY OBJECTIVES: To evaluate the effect of food on the bioavailability of itraconazole (ITR) hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solution under multiple-dose to steady-state conditions, and to determine the pharmacokinetics of ITR solution at steady state. DESIGN: Open-label, randomized, multiple-dose, crossover study SETTING: University-affiliated health center. PATIENTS: Thirty healthy men randomized to one of two treatment sequences (fasted-fed, fed-fasted). INTERVENTIONS: Subjects were either fasted or fed a standard breakfast before receiving ITR oral solution 200 mg once/day for 15 days. Crossover phases were separated by a 4-week washout period. MEASUREMENTS AND MAIN RESULTS: On day 1, blood samples were collected before the dose (time zero) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours after the dose. Trough samples were obtained before the dose on days 4, 7, 12, 13, and 14. On day 15, samples were obtained at the same times as day 1, and at 36, 48, 72, 96, 168, 240, and 360 hours. Samples were analyzed by high-performance liquid chromatography for ITR and its major metabolite hydroxyitraconazole (OH-ITR). Urine was collected on days 1 and 15 before and 0-8 and 8-24 hours after the dose; HP-beta-CD was measured by size-exclusion chromatography. Mean bioavailabilities of ITR and OH-ITR were 43% and 38% higher, respectively, when ITR solution was taken as a single dose under fasted conditions. With multiple dosing, steady state was achieved by day 14. At steady state, mean bioavailabilities were 29% and 17% higher, respectively, in the fasted state; terminal half-life was similar under fasted and fed conditions (mean 39.8 and 37.5 hrs for ITR, respectively; 27.3 and 26.2 hrs for OH-ITR, respectively). HP-beta-CD was eliminated almost exclusively in urine. CONCLUSION: The bioavailability of ITR and OH-ITR is enhanced when ITR oral solution is given in the fasted state; this was true for both single and multiple dosing to steady state.