Itraconazole trough concentrations in antifungal prophylaxis with six different dosing regimens using hydroxypropyl‐β‐cyclodextrin oral solution or coated‐pellet capsules

Abstract

We have previously shown that a trough concentration of at least 500 ng ml-1 itraconazole is necessary for an effective antifungal prophylaxis in neutropenic patients. Since the bioavailability of itraconazole is reduced in these patients, a satisfactory dosing regimen remains to be defined. In this study, six dosing regimens with itraconazole capsules 400, 600 or 800 mg day-1, itraconazole solution 400 mg day-1 (additional loading dose: 400 mg day-1 solution for 2 days), 800 mg day-1 or 400 mg day-1 (additional loading dose: 800 mg day-1 capsules for 7 days, s/c1200) were compared during 160 courses of myelosuppressive chemotherapy in 123 patients with acute leukaemia. After the first week, patients taking 800 mg day-1 or 400 mg day-1 (s/c1200) itraconazole solution achieved significantly higher trough concentrations (high-performance liquid chromatography) than patients in other groups (P < 0.05) and 87 and 100%, respectively, of these had concentrations > 500 ng ml-1. Contrary to a dose of 400 mg day-1, a dose of 800 mg day-1 itraconazole solution induced severe nausea and vomiting in 46% of the patients. We conclude that 400 mg day-1 itraconazole solution with a loading dose of 800 mg day-1 capsules for 7 days resulted in sufficient trough concentrations from the first week onwards and appears to be suitable for antifungal prophylaxis in neutropenic patients.

Current Concepts in Antifungal Pharmacology

“…86 Mold-active triazole antifungal agents (itraconazole, voriconazole, and posaconazole) are the other antifungal class most frequently recommended for TDM because of erratic absorption (itraconazole and posaconazole), variable hepatic clearance (voriconazole), and propensity for multiple drug interactions. 86 Several studies have examined the association between itraconazole efficacy and serum drug levels when the drug is administered as prophylaxis 90,91 or for the treatment 5,92-94 of documented infections due to Candida, Aspergillus, Cryptococcus, and Coccidioides immitis. All of these studies found a higher probability of treatment response when serum trough concentrations determined by bioassay surpassed 6 μg/ mL (>1-2 μg/mL by high-performance liquid chromatography).…”

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…55 Variations in gastric acidity and the widespread use of proton pump inhibitors in HSCT recipients may decrease absorption of itraconazole. Therefore, use of itraconazole oral solution in these patients, which produces higher serum trough concentrations, 56 is preferred.…”

Invasive Fungal Infections in Patients with Acute Leukemia and Hematopoietic Stem Cell Transplant Recipients

“…Multiple studies have explored whether these variations have clinical consequences in terms of efficacy. Itraconazole oral formulations have been seen to have variable bioavailability in multiple studies [141][142][143][144][145]. Higher doses appear to have greater antrifungal effects in both animals and humans [141,[145][146][147][148] .…”

“…Itraconazole oral formulations have been seen to have variable bioavailability in multiple studies [141][142][143][144][145]. Higher doses appear to have greater antrifungal effects in both animals and humans [141,[145][146][147][148] . Voriconazole , when taken orally also has been shown to havevariable bioavailability, especially in HCT recipients [149][150][151].Voriconazole is metabolized in the liver via the cytochrome P450 dependent mechanism, predominantly by CYP2C19 isoenzyme which exhibits genetic polymorphism resulting in reduced drug metabolism in 15-20% patients of Asian descent, and 3-5% of Caucasians and Blacks [150].…”