Itraconazole solution: higher serum drug concentrations and better clinical response rates than the capsule formulation in acquired immunodeficiency syndrome patients with candidosis.

Abstract

Aims-To compare the serum concentrations of itraconazole and hydroxyitraconazole after treatment with itraconazole cyclodextrin solution and itraconazole capsules in human immunodeficiency virus (HIV) positive patients with oral candidosis. Methods-The pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole were assessed on days 1 and 7 of therapy in aquired immunodeficiency syndrome (AIDS) patients with oral candidosis taking either itraconazole solution or capsules and the serum concentrations (measured by high performance liquid chromatography) correlated with the clinical response to therapy. In addition, the in vitro susceptibility of Candida spp isolates taken from patients at the start of the therapy was assessed. Results-Nine of 16 patients treated with itraconazole capsules and eight of 15 treated with the solution responded to treatment. Three of the non-responders in each treatment group were infected with isolates resistant to itraconazole in vitro. Although with both preparations there was considerable inter-patient variability in the maximum recorded serum concentrations of itraconazole, they were significantly lower on day 1 and day 7 in those receiving capsules compared with those taking the solution. Patients unresponsive to therapy, but infected with susceptible isolates, had significantly lower concentrations of itraconazole and hydroxyitraconazole levels on days 1 and 7 than patients responding to treatment. However, patients infected with itraconazole resistant isolates (tested in vitro) failed to respond to treatment despite achieving similar serum concentrations of itraconazole and hydroxy-itraconazole to the responsive patients. For patients with in vitro susceptible isolates a serum itraconazole concentration of < 1000 nglml on day 7 was predictive of therapeutic failure (specificity 71%, sensitivity 100%). Conclusions-Itraconazole cyclodextrin solution achieves higher serum itraconazole and hydroxy-itraconazole concentrations than the capsule formulation in AIDS patients, and this is associated with improved efficacy.

In Vitro Susceptibilities of Clinical Isolates of Candida Species, Cryptococcus neoformans , and Aspergillus Species to Itraconazole: Global Survey of 9,359 Isolates Tested by Clinical and Laboratory Standards Institute Broth Microdilution Methods

“…The development of itraconazole as an important antifungal agent has lagged due to the lack of an IVF and the poor and erratic bioavailability of the oral capsule formulation (2,5,29,39). Although bioavailability was much improved with the oral solution, it remains somewhat variable and is clearly inferior to that of fluconazole or voriconazole (2,29,36,39).…”

“…Whereas the suggested "target" concentration of Ն0.5 g/ml in serum (29,30) was difficult to achieve reliably with either oral formulation, it is now very easy to obtain peak concentrations of 2 to 4 g/ml and troughs of Ն1 g/ml using the IVF (4,19,29,36,39). Although itraconazole has often been used as a comparator in surveys of the in vitro antifungal susceptibility of opportunistic fungal pathogens, it has rarely been the primary focus of such studies; thus, its activity against opportunistic fungi is generally underappreciated (5,8,9,13,22,24,25). In part, this may also be due to a perception of rather poor activity of itraconazole against Candida spp.…”

“…Despite the wellfounded enthusiasm for the new antifungal agents, it is important to continue to assess the activity of the older, more established agents, especially those, such as itraconazole, for which the development of new formulations has overcome some of the major deficiencies (i.e., bioavailability) of the drug when it was first introduced (2-5, 10, 16, 18, 19, 29, 36, 39, 40). The inherent potency and broad spectrum of itraconazole (1,5,13,16,17,22,24,29,38), coupled with the availability of an intravenous formulation (IVF), suggests that the use of itraconazole as first-line therapy for some of the opportunistic mycoses may well become an option (29).…”

Optimizing antifungal choice and administration

“…The capsular form of itraconazole is associated with wide variability [27][28][29] , with markedly lower absorption and plasma concentrations when administered under fasting versus fed conditions 30,31 . Itraconazole solution demonstrates more predictable absorption and higher plasma concentrations compared to the itraconazole capsule formulation, particularly under fasting conditions 32,33 . Administration of itraconazole capsules with an acidic beverage has been shown to enhance absorption.…”

Clinical Significance of Measuring the Blood Concentration of Itraconazole Oral Solution in the Field of Hematology

“…On the other hand, several studies involving the administration of ITCZ injection, capsules, and OS to patients with neutropenia reported that the blood level of ITCZ in a steady state after ITCZ-OS administration was 15 times higher than those after the administration of ITCZ injection/capsules. 6,[11][12][13] Therefore, when administering ITCZ-OS, which is more rapidly absorbed in the digestive tract compared to its conventional dosage forms, to patients with blood diseases, the blood concentration of ITCZ should be measured to maintain its efficacy and safety.…”