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Itraconazole (ITZ) is one of the broad-spectrum antifungal agents for treating fungal keratitis. In clinical use, ITZ has problems related to its poor solubility in water, which results in low bioavailability when administered orally. To resolve the issue, we formulated ITZ into the inclusion complex (ITZ-IC) system using β-cyclodextrin (β-CD), which can potentially increase the solubility and bioavailability of ITZ. The molecular docking study has confirmed that the binding energy of ITZ with the β-CD was -5.0 kcal/mol, indicating a stable conformation of the prepared inclusion complex. Moreover, this system demonstrated that the inclusion complex could significantly increase the solubility of ITZ up to 4-fold compared to the pure drug. Furthermore, an ocular drug delivery system was developed through dissolving microneedle (DMN) using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA) as polymeric substances. The evaluation results of DMN inclusion complexes (ITZ-IC-DMN) showed excellent mechanical strength and insertion ability. In addition, ITZ-IC-DMN can dissolve rapidly upon application. The ex vivo permeation study revealed that 75.71% (equivalent to 3.79 ± 0.21 mg) of ITZ was permeated through the porcine cornea after 24 h. Essentially, ITZ-IC-DMN exhibited no signs of irritation in the HET-CAM study, indicating its safety for application. In conclusion, this study has successfully developed an inclusion complex formulation containing ITZ using β-CD in the DMN system. This approach holds promise for enhancing the solubility and bioavailability of ITZ through ocular administration.

Conventional itraconazole (c-ITZ) can be used for a variety of fungal infections although variable absorption has been a significant limitation. Super-bioavailable itraconazole (SUBA-ITZ) is a novel formulation that overcomes absorption concerns by utilizing a polymer-matrix to disperse active drug and facilitate dissolution. The pH-driven matrix allows concurrent proton pump inhibitor administration without significant effects on drug concentrations. The enhanced bioavailability of SUBA-ITZ allows for lower dosing, while achieving similar serum concentrations as c-ITZ and SUBA-ITZ is now US FDA approved in the treatment of blastomycosis, histoplasmosis and aspergillosis. Common side effects of SUBA-ITZ include gastrointestinal disorders, peripheral edema and drug-induced hypertension. Given the significant differences in pharmacokinetics between the formulations, c-ITZ and SUBA-ITZ capsules are not considered interchangeable. It is important to note that drug errors may occur when transitioning a patient from one formulation to another.

Itraconazole (ITZ) is the most used drug to treat feline sporotrichosis; however, little is known about its pharmacokinetics in cats with this mycosis. The aim of this study was to determine plasma ITZ concentrations in cats with sporotrichosis treated with ITZ as monotherapy or in combination with potassium iodide (KI). Cats diagnosed with sporotrichosis received orally ITZ (100 mg/cat/day) or combination therapy with ITZ (100 mg/cat/day) and KI (2.5-5 mg/kg/day) in the case of worsening or stagnation of the clinical condition. At each monthly visit, blood samples were collected at an interval of 4 h for analysis of trough and peak plasma ITZ concentrations by HPLC. Clinical features and laboratory parameters were evaluated during follow-up. Sixteen cats were included in the study. The median plasma ITZ concentration of all cats was 0.75 µg/mL. The median plasma ITZ concentration was 0.5 µg/mL in cats that received ITZ monotherapy (n = 12) and 1.0 µg/mL in those treated with ITZ + KI (n = 4). The clinical cure rate was 56.3% (n = 9) and the median treatment duration was 8 weeks. Nine cats (56.3%) developed adverse clinical reactions, and hyporexia was the most frequent (n = 8; 88.9%). Serum alanine aminotransferase was elevated in four cats (25%). The median plasma ITZ concentration detected in cats was considered to be therapeutic (>0.5 µg/mL) and was reached after 4 weeks of treatment. Plasma ITZ concentrations were higher in cats that received ITZ + KI compared to those treated only with ITZ, suggesting pharmacokinetic synergism between these drugs., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Background: Invasive fungal infections (IFIs) are severe and difficult-to-treat infections affecting immunocompromised patients. Antifungal drug penetration at the site of infection is critical for outcome and may be difficult to achieve. Data about antifungal drug distribution in infected human tissues under real circumstances of IFI are scarce., Methods: Multiple samples were obtained from soft tissue abscesses of a lung transplant patient with Candida albicans invasive candidiasis who underwent recurrent procedures of drainage, while receiving different consecutive courses of antifungal therapy [itraconazole (ITC), fluconazole, caspofungin]. Antifungal drug concentrations were measured simultaneously at the site of infection (surrounding inflammatory tissue and fluid content of the abscess) and in plasma for calculation of the tissue/plasma ratio (R). The concentration within the infected tissue was interpreted as appropriate if it was equal or superior to the MIC of the causal pathogen., Results: A total of 30 tissue samples were collected for measurements of ITC (n = 12), fluconazole (n = 17) and caspofungin (n = 1). Variable concentrations were observed in the surrounding tissue of the lesions with median R of 2.79 (range 0.51-15.9) for ITC and 0.94 (0.21-1.37) for fluconazole. Concentrations ranges within the fluid content of the abscesses were 0.39-1.83 for ITC, 0.66-1.02 for fluconazole and 0.23 (single value) for caspofungin. The pharmacodynamic target (tissue concentration ≥ MIC) was achieved in all samples for all three antifungal drugs., Conclusions: This unique dataset of antifungal drug penetration in infected human soft tissue abscesses suggests that ITC, fluconazole and caspofungin could achieve appropriate concentrations in soft tissue abscesses., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Immunocompromised patients are susceptible to fungal infections, and drug-drug interactions with antifungals may occur due to concomitant medications. Fosmanogepix [FMGX; active moiety manogepix (MGX)] targets glycosylphosphatidylinositol-anchored mannoprotein synthesis and maturation, essential for fungal virulence. This phase 1, fixed-sequence study in healthy participants evaluated the effect of strong CYP3A4 inhibitor itraconazole [Cohort 1 ( n = 18); FMGX 500 mg intravenous (IV) twice a day (BID )+ itraconazole 200 mg oral once a day (QD)] and pan-CYP inducer rifampin [Cohort 2 ( n = 18); FMGX 1,000 mg IV BID + rifampin 600 mg oral QD] on the pharmacokinetics of FMGX and MGX. In cohort 1, geometric mean (GM) MGX C max , AUC 0-t , and AUC inf were almost similar with and without itraconazole administration. In Cohort 2, GM MGX C max was slightly lower and AUC 0-t and AUC inf were significantly lower after rifampin administration, with the least squares GM ratio associated 90% confidence intervals (CIs) below 80 - 125% (no effect window). No deaths, serious adverse events (SAEs), or FMGX-related withdrawals were reported. In both cohorts, a total of 188 AEs ( n = 30; 186 mild; two moderate) were reported. In all, 37 of 188 AEs ( n = 12) were considered FMGX related (most frequent: headache, nausea, and hot flush). Administration of FMGX alone and with itraconazole or rifampin was safe and well tolerated. A strong CYP3A4 inhibitor had no effect on FMGX or MGX exposure. A strong pan-CYP inducer had no effect on FMGX exposure but demonstrated ~45% decrease in MGX exposure., Clinical Trials: This study is registered with ClinicalTrials.gov as NCT04166669 and with EudraCT as number 2019-003586-17., Competing Interests: M.R.H. and E.O. were employees of Amplyx (now a Pfizer Inc. subsidiary). M.R.H. was previously an employee of Pfizer and holds Pfizer stock. A.J. and M.T. are Pfizer employees and hold Pfizer stock. S.V.M. is an employee of ICON (formerly PRA Health Sciences). W.G.K. was a paid consultant for Amplyx for this study.

Lumacaftor/ivacaftor (Orkambi®, LUM/IVA) is indicated for the treatment of cystic fibrosis (CF) patients aged ≥ 2 years with homozygous F580del mutation in the CFTR gene. Triazole fungal agents are used to treat fungal disease in CF. The use of triazoles is limited by pharmacokinetic challenges, such as drug-drug interactions. The most notable drug-drug interaction between triazoles and LUM/IVA is due to strong induction of CYP3A4 and UGT by LUM. In this real-world retrospective observational study, we described the effect of LUM/IVA on the trough concentration of triazoles. Concomitant use of LUM/IVA with itraconazole, posaconazole or voriconazole resulted in subtherapeutic triazole levels in 76% of the plasma samples. In comparison, in patients with triazole agents without LUM/IVA only 30.6% of the plasma samples resulted in subtherapeutic concentrations. Subtherapeutic plasma concentrations of triazoles should be considered in CF patients on LUM/IVA and further research is warranted for other dosing strategies and alternative antifungal therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: With rising resistance to terbinafine, and consistently high MICs to fluconazole and griseofulvin, itraconazole is being increasingly used as a first line drug for tinea corporis/cruris. However, inadequate clinical responses are often seen with it in spite of in vitro susceptibility. This is possibly related to a variable pharmacokinetic profile of itraconazole. The drug serum levels associated with the therapeutic outcome have not been defined in dermatophytic infections., Methods: Forty treatment naïve patients with tinea corporis/cruris were randomised to one of the three dose groups (100, 200 and 400 mg/day) of itraconazole. The drug serum levels of 21 of these patients were obtained after 2 weeks of treatment and correlated with the final clinical outcome and in vitro antifungal susceptibility data., Results: Trichophyton indotineae was identified by sequencing of ITS region of rDNA and TEF1α. All isolates were sensitive to itraconazole (Minimum Inhibitory Concentration (MICs) range: 0.06-0.5 µg/ml), while MICs to terbinafine were uniformly high (range 8-32 µg/ml). Thirty-seven patients (92.5%) achieved complete cure, while three failed treatment. Serum levels achieved with 400 mg/day were significantly higher than levels with 100 or 200 mg dose. All patients with itraconazole serum levels of >0.2 µg/ml were cured, while two out of the 10 patients with serum levels <0.2 µg/ml failed treatment., Conclusions: Therapeutic failures are uncommon with itraconazole, and the prevalent strain in India has low itraconazole MICs. Treatment failure is likely with itraconazole serum levels of <0.2 µg/ml, while levels >0.2 µg/ml are consistently associated with a positive therapeutic outcome., (© 2021 Wiley-VCH GmbH.)

Purpose: Serum markers of renal function have not been characterized in patients treated with itraconazole (ITZ). This study aimed to evaluate the associations between plasma ITZ and its hydroxylated metabolite (OH-ITZ) concentrations and serum markers of renal function in patients with hematopoietic or immune-related disorder., Methods: This study enrolled 40 patients with hematopoietic or immune-related disorder who are receiving oral ITZ solution. Plasma concentrations of ITZ and OH-ITZ at 12 h after dosing were determined at steady state. Their relationships with serum levels of creatinine and cystatin C and their estimated glomerular filtration rate (eGFR) were evaluated., Results: The free plasma concentration of ITZ had no correlation with serum creatinine and serum creatinine-based estimated glomerular filtration rate (eGFR-cre). The free plasma concentration of OH-ITZ was positively and negatively correlated with serum creatinine and eGFR-cre, respectively. The free plasma concentrations of ITZ and OH-ITZ had no association with serum cystatin C and serum cystatin C-based eGFR. Serum creatinine was higher by 16% after than before starting ITZ treatment, while eGFR-cre was lower by 9.3%. The serum creatinine ratio after/before ITZ treatment was positively correlated with the free plasma concentration of OH-ITZ. The patients co-treated with trimethoprim-sulfamethoxazole had higher serum creatinine. Concomitant glucocorticoid administration did not significantly alter serum cystatin C., Conclusions: Patients with hematopoietic or immune-related disorder treated with oral ITZ had a higher level of serum creatinine. Although serum creatinine potentially increases in conjunction with the free plasma concentration of OH-ITZ, concomitant ITZ administration has a slight impact on the eGFR-cre level in clinical settings.

The objective of this study was to establish a single-dose pharmacokinetic profile for orally administered itraconazole in California sea lions (Zalophus californianus). Twenty healthy rehabilitated juvenile California sea lions were included in this study. Itraconazole capsules were administered orally with food at a target dose of 5-10 mg/kg. Blood samples were collected from each animal at 0 hr and at two of the following timepoints: 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72 hr. Quantitative analysis of itraconazole in plasma samples was performed by high-performance liquid chromatography. An average maximum concentration of 0.22 µg/ml ± 0.11 was detected 4 hr after administration. The average concentration fell to 0.12 µg/ml ± 0.11 by 6 hr and 0.02 µg/ml ± 0.02 at 12 hr. At no point did concentrations reach 0.5 µg/ml, the concentration commonly accepted for therapeutic efficacy. While this formulation was well tolerated by the sea lions, oral absorption was poor and highly variable among individuals. These data indicate that a single oral dose of itraconazole given as a capsule at 5-10 mg/kg, under the conditions used in this study, does not achieve therapeutic plasma concentrations in California sea lions., (© 2020 John Wiley & Sons Ltd.)

Aspergillosis is a common cause of morbidity and mortality in captive penguins. Itraconazole, an antifungal drug, is commonly used to treat aspergillosis infections in avian species; however, commercially available human formulations are costly, and studies have shown the effectiveness of compounded formulations to be unreliable. The US Food and Drug Administration (FDA) recently approved a veterinary formulation of itraconazole, Itrafungol, for use in cats. This study provides preliminary results from limited sampling evaluating whether this veterinary formulation is suitable for future studies in the African penguin ( Spheniscus demersus ). A 20 mg/kg PO itraconazole dose was administered to 9 African penguins. Blood samples were taken over the course of 24 hours; each sample was collected from a different bird to minimize stress to the animals. Plasma was analyzed by high-performance liquid chromatography for concentrations of itraconazole. The drug was absorbed in all penguins, and plasma concentrations in 5 of 9 penguins (56%) were found to be greater than the established therapeutic dose of 1.0 µg/ mL. To our knowledge, this is the first study that has investigated a 20 mg/kg dose of itraconazole in a penguin species. The small sample size limits the conclusions that can be drawn from this preliminary study. Nonetheless, we demonstrate encouraging evidence that the FDA-approved formulation of oral itraconazole solution should be considered for future study as a cost-effective treatment for aspergillosis in African penguins and other avian species.

Aim: Formulate and evaluate liquisolid compacts of Itraconazole, a biopharmaceutical classification system class II drug, which has poor bioavailability. Materials & methods: PEG 600 was used as a nonvolatile solvent, Alfacel PH 200 as a carrier and Aerosil 200 as a coating material. The Itraconazole solution upon mixing with a carrier and coating material resulted in a dry powder, which was compressed into tablets. Results & conclusion: The optimized formulation exhibited a significantly higher drug dissolution (90.73% in 90 min) compared with conventional tablets and marketed capsules. The antifungal activity was retained in the formulation. Higher values of C max and AUC 0-24 of the formulation compared with the plain drug indicated enhancement in oral bioavailability. The formulation was stable at room temperature as well as in accelerated conditions.

Solid dosage forms of amorphous solid dispersions (ASDs) have rarely been assessed for their crushability, although it might possibly be a more frequent practice than thought to facilitate oral administration in several clinical conditions (e.g. dysphagia) when no oral liquids of the same drug are available. Nevertheless, there are concerns that contraindicate these formulations' modification by grinding. For example, amorphous-amorphous phase separation, induction of crystallization, decreasing particle sizes, etc. might occur during grinding without knowing the implications on bioavailability. Hence, in this study, Sporanox® (itraconazole), Intelence® (etravirine), Noxafil® (posaconazole) and Norvir® (ritonavir), were selected as "model" enabling formulations (based on ASD) to evaluate if this concern was justified. Their assessment in simple and biorelevant media by two-stage in-vitro drug-release testing was performed which resulted in strong suspicion that pulverization is contradicted for some of these formulations. Despite differences were observed, uncertainty remains on the clinical relevance of these data as by golden standard it should still be confirmed by bioequivalence trials., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Dasatinib, as an oral multi-targeted inhibitor of BCR-ABL and SRC family kinases, has been widely used for the treatment of Philadelphia Chromosome Positive Leukemias in imatinib-acquired resistance and intolerance. The study aimed to develop and validate a simple and robust assay with a small volume of plasma based on liquid chromatography coupled with tandem mass spectrometry to determine the concentration of dasatinib and to investigate the impact of the cytochrome 3A4 inhibitors, including ketoconazole, voriconazole, itraconazole and posaconazole, on the pharmacokinetics of dasatinib in rats., Methods: Thirty rats were divided randomly into five groups, control group (0.5% carboxymethylcellulose sodium), ketoconazole (30 mg/kg) group, voriconazole group (30 mg/kg), itraconazole group (30 mg/kg) and posaconazole group (30 mg/kg). After 150 μL blood samples were collected at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h and precipitated with acetonitrile, the plasma concentration of dasatinib was determined through Fluoro- Phenyl column (150 mm×2.1 mm, 3 μm) in a positive ionization mode., Results: The results suggested that ketoconazole, voriconazole, and posaconazole could increase the AUC0-t of dasatinib to varying degrees while significantly reducing its clearance. However, there was no significant impact on the pharmacokinetics of dasatinib, co-administered with itraconazole except for the CL and MRT0-t of dasatinib. Additionally, voriconazole could significantly increase Cmax of dasatinib by approximately 4.12 fold., Conclusion: These data indicated that ketoconazole, posaconazole and voriconazole should be cautiously co-administered with dasatinib or close therapeutic drug monitoring of dasatinib concentration, which might cause the drug-drug interaction., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The emergence of drug-resistant fungal strains remains a severe threat for the public health, which prompts strict restrictions on the uses of antifungal drugs. However, the majority of lipophilic fungistatic agents are poorly water soluble with a low oral adsorption characteristic posing challenges for the precise prescriptions. In this study, a natural antimicrobial cationic peptide of epsilon-poly-l-lysine (EPL) decorated ordered mesoporous silica (SBA-15) was facilely prepared for the efficient loading of antifungal itraconazole (ITZ) drugs. The characterized mesoporous SBA-15/EPL/ITZ composite exhibited remarkable antifungal performance against Aspergillus fumigatus as a model mold, which was attributed to synergistic antifungal activities of ITZ and EPL in the mesopores. Moreover, the in vitro release behaviors of ITZ in the composite nanoexcipients both in simulated gastric fluid and fasted state simulated intestinal fluid were studied. The observed release kinetics of ITZ demonstrated a contributing role of SBA-15/EPL to enhance the solubility of ITZ and thereby may promote its flux across the gastrointestinal epithelium, which is beneficial for the absorption of drugs. Additionally, SBA-15/EPL/ITZ composites showed desirable biocompatibility toward mammalian red blood cells, human cervical cancer cells (Hela) and human embryonic kidney cells (HEK-293T). Furthermore, the pharmacokinetic profiles of obtained nano-formulations were assessed in rats, among which the improved adsorption of SBA-15/EPL/ITZ composites (AUC 0-24h sum : 8381.7 nM·h) was identified compared with that of pure ITZ (525.1 nM·h) and the commercial drug of Sporanox (7516.6 nM·h). Collectively, the prepared SBA-15/EPL/ITZ provides an ecofriendly and integrated nanocomposite with enhanced solubility of lipophilic drugs to combat proliferations of infectious fungi., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Recalcitrant dermatophytoses is on the rise. Though myriad factors contribute to recalcitrance including terbinafine resistance, itraconazole largely remains sensitive. However, there are increasing instances of patients not responding adequately to itraconazole despite low MICs, probably due to issues plaguing the pelletization process, resulting in suboptimal quality. Data on this topic was searched on pubmed using the search items: itraconazole, MIC, MFC, quality, assay, pharmacokinetics, pharmacodynamics, dermatophytoses, and recalcitrance. Areas covered: A detailed analysis of the manufacturing process of itraconazole with emphasis on pelletization and parameters affecting the dissolution and bioavailability is presented. Important formulation factors including drug-polymer ratio, polymer type, coating thickness, bead size, and number are discussed. Also covered is the rationale of dosimetry of itraconazole in dermatophytoses based on the skin pharmacokinetics and MIC of the organism. Expert opinion: The process of pelletization has multiple components aiming to achieve maximum dissolution of the drug. Variations in the process, pellet quality, number, and polymer determine absorption. Morphometric analysis of pellets is a simple method to quantify quality of the drug. Once the process has been standardized, dosimetry depends on the route of secretion and site of infection, accounting for the variation of doses from 100 mg to 400 mg/day.

Background and Objective: SUBA-itraconazole and Sporanox are two oral formulations of itraconazole. Drug-drug interactions with omeprazole have been previously reported; however, mechanistic understanding of the pharmacological and physiological interactions of omeprazole with orally administered itraconazole within a population modeling paradigm is lacking. The objective of this analysis was to mechanistically describe and quantify the effect of omeprazole on the pharmacokinetics of itraconazole and its major metabolite, hydroxyitraconazole from the SUBA itraconazole and Sporanox formulations., Methods: An in vitro-in vivo (IVIV) pharmacokinetic model of itraconazole and hydroxyitraconazole was developed including data from an omeprazole interaction study with SUBA itraconazole. Meta-models of gastric pH for healthy subjects and subjects receiving omeprazole were integrated into the IVIV model to capture omeprazole-mediated gastric pH changes on itraconazole dissolution and absorption., Results: Omeprazole influenced the kinetics of itraconazole through altering the dissolution and absorption due to the pH-dependent solubility of itraconazole, inhibition of efflux transporters, and inhibiting the metabolism of itraconazole and hydroxyitraconazole. The model-predicted population effects of omeprazole on itraconazole from SUBA-itraconazole were to increase the area under the concentration-time curve (AUC 0-24 ) and maximum concentration (C max ) by 35 and 31%, respectively, and to decrease AUC 0-24 and C max from Sporanox by 68 and 76%, respectively., Conclusion: Unlike SUBA itraconazole, which requires basic pH for itraconazole release, the omeprazole-induced pH-mediated reduction in Sporanox dissolution overrides any increased exposure from the drug-drug interaction at hepatic metabolizing enzymes or efflux transporters. The model presented here is the most complete quantitative description of the pharmacokinetics of itraconazole and hydroxyitraconazole currently available.

Background: Itraconazole is a broad-spectrum antifungal agent used for prophylaxis and treatment of fungal infections in immunocompromised children. Achieving the recommended target serum itraconazole trough concentration of ≥0.5 mg/L is challenging in children because of variation in itraconazole pharmacokinetics with age. We studied itraconazole use and treatment outcomes in a tertiary children's hospital., Methods: We did a 10-year retrospective review of medical records of children at the Royal Children's Hospital Melbourne who received oral itraconazole and had therapeutic drug monitoring (TDM)., Results: Overall, 81 children received 92 courses of oral itraconazole and had TDM. Of 222 TDM samples, 183 (82.4%) were taken at the appropriate time (trough level at steady state). Patients ≤12 and >12 years of age required median doses of 6.2 and 3.9 mg/kg/d, respectively, to attain target trough levels (P < 0.001). Of children ≤12 years of age, 71.4% required doses above the recommended dose of 5 mg/kg/d to achieve therapeutic levels, compared with 17.4% of those >12 years of age. At least 1 subtherapeutic trough concentration was reported in 63 (76.8%) courses; in only 18 (28.6%) of these was the dose adjusted. Gastrointestinal symptoms [14/92 (15.2%) courses] and hepatotoxicity [6/92 (6.5%)] were the most frequent adverse events. Neither was associated with elevated trough levels., Conclusions: The poor attainment of target levels with current recommended dosing in children <12 years of age suggests that higher empiric doses are needed in this age group. The poor compliance with TDM guidelines highlights the need for better education about appropriate timing of sampling and dose adjustment.

Aspergillosis is an infectious, non-contagious fungal disease of clinical importance in flamingo collections. Itraconazole is an antifungal drug commonly used in the treatment and prophylaxis of avian aspergillosis. Studies have shown that dosage regimes in birds vary based on different itraconazole presentation and administration methods. This investigation used a population pharmacokinetic approach to study itraconazole in lesser flamingos. Itraconazole was administered orally at 10 mg/kg to 17 flamingos. A sparse blood sampling was performed on the subjects, and samples were collected at 1, 2, 3, 5, 8, 12, 16, 21, and 24 hr post-drug administration. Twelve flamingos were sampled three times, three birds bled twice and two sampled once. Itraconazole in plasma was quantified using high-pressure liquid chromatography (HPLC). A one-compartment pharmacokinetic model with first order absorption was fitted to the data using nonlinear mixed effects modeling (NLME) to determine values for population parameters. We identified a long half-life (T½) of more than 75 hr and a maximum plasma concentration (C MAX ) of 1.69 µg/ml, which is above the minimal inhibitory concentrations for different aspergillus isolates. We concluded that plasma drug concentrations of itraconazole were maintained in a population of flamingos above 0.5 ug/ml for at least 24 hr after a single oral dose of 10 mg/kg of itraconazole solution., (© 2018 John Wiley & Sons Ltd.)

A copolymeric micelle formulation of itraconazole (ITR-M) was prepared using linear-dendritic monoallyloxy poly (ethylene glycol)-b-poly (ε-caprolactone) (APEG-PCL) as drug carrier materials. DL and EE values of ITR-M were 5.70 ± 0.12% and 91.30 ± 1.90%, respectively. The micelle formulation enhanced the ITR solubility up to 30.42 μg/mL. In vitro release of ITR from the ITR-M was mainly drug diffusion process followed by the copolymer's degradation. ITR-M showed similar anti-Candida albicans activity to that of crude ITR although its release of ITR was slow and continuous. The in vivo pharmacokinetic study demonstrated that the ITR-M could improve tissue distribution of ITR. In conclusion, APEG-PCL could be a potential carrier in the development of antifungal drug delivery system.

To address the limited bioavailability and intolerance of the conventional itraconazole (ITZ) formulations, a new formulation labeled su per b io a vailability (SUBA) itraconazole has been developed; however, the specific effects of food and gastric pH are unknown. This study evaluated the pharmacokinetic profile of SUBA itraconazole under fasting and fed conditions, as well as with the concomitant administration of a proton pump inhibitor. First, the effect of food was assessed in an open-label, randomized, crossover bioavailability study of 65-mg SUBA itraconazole capsules (2 65-mg capsules twice a day) in healthy adults ( n = 20) under fasting and fed conditions to steady-state levels. Second, an open-label, two-treatment, fixed-sequence comparative bioavailability study in healthy adults ( n = 28) under fasted conditions compared the pharmacokinetics of a single oral dose of SUBA itraconazole capsules (2 65-mg capsules/day) with and without coadministration of daily omeprazole delayed-release capsules (1 40-mg capsule/day) under steady-state conditions. In the fed and fasted states, SUBA itraconazole demonstrated similar concentrations at the end of the dosing interval, with modestly lower total and peak ITZ exposure being shown when it was administered under fed conditions than when it was administered in the fasted state, with fed state/fasted state ratios of 78.09% (90% confidence interval [CI], 74.49 to 81.86%) for the area under the concentration-time curve over the dosing interval (14,183.2 versus 18,479.8 ng · h/ml), 73.05% (90% CI, 69.01 to 77.33%) for the maximum concentration at steady state (1,519.1 versus 2,085.2 ng/ml), and 91.53% (90% CI, 86.41 to 96.96%) for the trough concentration (1,071.5 versus 1,218.5 ng/ml) being found. When dosed concomitantly with omeprazole, there was a 22% increase in the total plasma exposure of ITZ, as measured by the area under the concentration-time curve from time zero to infinity (P  =  0.0069), and a 31% increase in the peak plasma exposure of ITZ, as measured by the maximum concentration (P  =  0.0083)., (Copyright © 2018 American Society for Microbiology.)

Formulating poorly water-soluble drug, itraconazole (ITZ), as dry powder inhaler (DPI) may be more effective for the treatment of invasive pulmonary Aspergillosis than intravenous injection and oral administration. It is necessary to improve the dissolution of ITZ because the alveolar lining fluid is limited and thus the dissolution of ITZ in the lung may be slow and incomplete. However, too fast dissolution may result in over-absorption into the circulation and thus insufficient distribution in the lung. The purpose of this study is to understand the relationship between in-vitro dissolution and in-vivo distribution of ITZ from DPI formulations. Two DPI formulations (F1 and F2) with identical compositions and similar aerodynamic behaviors were fabricated by hot melt extrusion and thus jet-milling. ITZ was formulated with mannitol as fine solid crystal suspension system to effectively improve its dissolution. In-vitro dissolution tests and in-vivo pharmacokinetic studies indicated that F1 released faster than F2 under both sink and non-sink conditions, but exhibited a lower lung retention and higher plasma absorption than F2. These results suggested that although dissolution enhancement of poorly water-soluble drugs in pulmonary delivery may be necessary to overcome problems such as local irritation and quick elimination by macrophages, it may have an impact on the distribution of the drug between the lung and the plasma. A balance between airway dissolution and systemic absorption should be taken into consideration when developing DPI formulations of poorly water-soluble ITZ., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In a previously performed small-scale clinical study, healthy volunteers were asked to ingest an oral solution of itraconazole (Sporanox ® ) containing 40% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) (i) with or (ii) without a standardized volume of water (240 mL) after which gastrointestinal and blood samples were collected. Although omitting water during the administration of Sporanox ® resulted in noticeably higher duodenal concentrations of itraconazole, systemic exposure was almost unaffected. It is assumed that this discrepancy can be explained by differences in the extent of entrapment of itraconazole in the duodenum caused by differential complexation depending on the concentration of cyclodextrins. To further substantiate this hypothesis, the quantification of HP-β-CD concentrations in the aspirated intestinal fluids was performed by LC-MS/MS. When comparing the intestinal concentrations of itraconazole and HP-β-CD for one single healthy volunteer (HV02) in both test conditions, an excellent correlation was observed (Spearman's rank coefficient of 0.96). Moreover, the data suggest that, similar to aqueous buffer media, also in human intestinal fluids a non-linear relationship exists between itraconazole solubility and HP-β-CD concentration (A p -type profile; Spearman's rank coefficient of 0.78), indicating that higher order complexes are formed at higher concentrations of HP-β-CD. This difference in extent of entrapment in the inclusion complexes helps to understand the observed impact of water intake on precipitation and permeation behavior of itraconazole in man. Without water intake, higher HP-β-CD concentrations resulted in less precipitation and increased duodenal concentrations of itraconazole. On the other hand, the stronger interaction at higher HP-β-CD concentrations reduced the free fraction of the drug explaining that increased intraluminal concentrations of itraconazole were not translated into an enhanced uptake. In conclusion, quantifying the concentrations of the solubilizing agent HP-β-CD in human intestinal fluids appeared to be of crucial importance to interpret the intraluminal behavior of an orally administered cyclodextrin-based solution., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The aim of the study was to evaluate the bioequivalence of two itraconazole 100 mg capsule formulations., Research Design and Methods: The single-center, open-label, randomized, three-period, three-sequence, reference-replicated, cross-over study included 38 healthy subjects under fed conditions. In each study period (separated by a 14-day washout), a single oral dose of the test (T) or reference (R) product was administered. Blood samples were collected at pre-dose and up to 72.0 h after administration. The calculated pharmacokinetic parameters, based on the plasma concentrations of itraconazole and hydroxy itraconazole, were AUC 0-72h , AUC 0-∝ , C max , T max , T 1/2 and K el ., Results: The 90% CI for the test/reference geometric means ratio for the parent compound, itraconazole, was in the range from 85.29% to 116.07% for AUC 0-72h. Since the coefficient of variation (CV) for the reference product was 44.95% for C max , the 90% CI for this parameter for itraconazole was 93.49-133.78%, which was within the proposed limits of the EMA for bioequivalence of 72.15-138.59%. During the study, 4 subjects encountered a total of 14 mild adverse events., Conclusions: The use of the reference-scaling approach with 3-period design (TRR, RTR, and RRT) was an efficient way to demonstrate that two commercially available oral itraconazole formulations met the predetermined bioequivalence criteria.

The triazole antifungal itraconazole may be cost prohibitive in brand name form; therefore, compounded and generic products are often used as alternatives. Itraconazole blood concentrations have not been studied in clinical patients receiving these formulations. Itraconazole bioassay was performed on serum/plasma from 95 dogs and 20 cats receiving itraconazole (compounded from bulk powder, generic pelletized, or brand name) for systemic mycosis treatment. Mean itraconazole concentration was lower in the compounded group (n = 42) as compared with the generic (n = 40) or brand name (n = 33) groups (0.5 µg/mL versus 8.3 µg/mL and 6.5 µg/mL, respectively; P < .001). No statistical difference was observed between itraconazole concentrations in the generic and brand name groups. Forty animals (95.2%) in the compounded group had subtherapeutic (<1.0 µg/mL) values. All cats in this group (n = 10) had undetectable itraconazole concentrations. Some animals in the generic and brand name groups had subtherapeutic values (12.5 and 12.1%, respectively) or potentially toxic values (>10 µg/mL; 37.5 and 24%, respectively). Compounded itraconazole should be avoided, but generic itraconazole appears to serve as a reasonable alternative to brand name itraconazole. Therapeutic drug monitoring may be beneficial in all cases.

The formulation factors relevant to developing immediate and controlled release dosage forms containing poorly soluble drugs dispersed in amorphous systems are poorly understood. While the utility of amorphous solid dispersions is becoming apparent in the pharmaceutical marketplace, literature reports tend to concentrate on the development of solid dispersion particulates, which then must be formulated into a tablet. Amorphous solid dispersions of itraconazole in high molecular weight hydroxypropyl methylcellulose were prepared by KinetiSol® Dispersing and tablets were formulated to immediately disintegrate or control the release of itraconazole. Formulated tablets were evaluated by two non-sink dissolution methodologies and the dosage form properties that controlled the gelling tendency of the dispersion carrier, hydroxypropyl methylcellulose, were investigated. Selected formulations were evaluated in an exploratory beagle dog pharmacokinetic study; the results of which indicate potential for a prolonged absorption phase relative to the commercially extruded control.

Purpose: The goal of the study was to evaluate a miniaturized dissolution-permeation apparatus (μFLUX™ apparatus) for its ability to benchmark several itraconazole (ITZ) formulations for which in vivo PK data was available in the literature., Method: Untreated and micronized powders of ITZ and various enabling formulations of ITZ (commercial Sporanox® solid dispersion, a Soluplus®-based solid dispersion and a nanosuspension) were introduced to the donor compartment of μFLUX™ apparatus. Donor and acceptor chambers were divided from each other by a lipophilic membrane. In addition to the flux evaluations, changes in solid state as a function of time were investigated to gain further insight into the flux changes observed over time for the solid dispersion formulations., Results: Initial flux values from Sporanox®, the nanosuspension and the micronized ITZ showed ratios of 52/4/1 with a decreasing flux from nanosuspension and both solid dispersions after 2.5-3 h. Although the initial flux from the Soluplus® formulation was 2.2 times lower than the one observed for Sporanox®, the decrease in flux observed was milder and became ~ 2 times higher than Sporanox® after approximately 2.5 h. The total amounts of ITZ in the receiver compartment after 240 min showed the same rank order as the rodent AUCs of these formulations reported in literature., Conclusions: It was demonstrated that in vitro flux measurements using lipophilic artificial membranes could correctly reproduce the rank order of PK results for ITZ formulations. The drop in flux over time for solid dispersions could be backed by experimental indications of crystallization.

The aim of this study was to develop a population in vitro-in vivo pharmacokinetic model that simultaneously describe the absorption and accumulation kinetics of itraconazole (ICZ) and hydroxy-itraconazole (HICZ) in healthy subjects. The model integrated meta-models of gastrointestinal pH and gastrointestinal transit time and in vitro dissolution models of ICZ with the absorption and disposition kinetics of ICZ and HICZ. Mean concentration intravenous data, and single- and multi-dose oral data were used for model development. Model development was conducted in NONMEM in a stepwise manner. First, a model of intravenous data (systemic kinetics) was established and then extended to include the oral data. The latter was then extended to establish the in vitro-in vivo pharmacokinetic model. The systemic disposition of ICZ was best described by a 3-compartment model with oral absorption described by 4-transit compartments and HICZ distribution by a 1-compartment model. ICZ clearance was best described using a mixed inhibition model that allowed HICZ concentrations to inhibit the clearance of parent drug. HICZ clearance was described by Michaelis-Menten elimination kinetics. An in vitro-in vivo model was successfully established for both formulations. The presented model was able to describe ICZ and HICZ plasma concentrations over a wide range of oral and intravenous doses and allowed the exploration of complexities associated with the non-linear ICZ and HICZ kinetics. The model may provide insight into the variability in exposure of ICZ with respect to relating in vivo dissolution characteristics with in vivo disposition kinetics.

OBJECTIVE To compare absorption characteristics of orally administered compounded itraconazole capsules and suspension with those of reference (brand-name) formulations in healthy cats. DESIGN Randomized crossover study. ANIMALS 8 healthy adult cats. PROCEDURES After 12 hours of food withholding, cats received 50 mg of itraconazole (reference capsule, reference solution, compounded capsule, and compounded suspension) in a randomized crossover design, with a 21-day washout period. Capsules were administered with a small meal. Blood samples were collected at predetermined intervals for high-pressure liquid chromatography analysis of plasma itraconazole concentrations. Area under the concentration-time curve, maximum concentration, and terminal half-life of itraconazole were determined and compared among formulations. RESULTS 7 cats completed the study. Mean half-life of itraconazole in reference formulations was 18 to 26 hours. Absorption of the reference solution was 3 times that of the reference capsule. Compounded formulations were absorbed poorly and inconsistently. Complete pharmacokinetic results for the compounded capsule were obtained for only 3 of 6 cats and for the compounded suspension for only 1 of 5 cats, precluding bioequivalence analysis. Relative absorption of compounded formulations was only 2% to 8% of reference formulation values. CONCLUSIONS AND CLINICAL RELEVANCE Compounded oral formulations of itraconazole should not be used for cats because of poor absorption. The differences in absorption between the 2 reference formulations suggested that doses required to meet human target serum concentrations in cats are markedly different (capsules, 12.5 mg/kg [5.7 mg/lb], q 24 h, with food; solution, 4 mg/kg [1.8 mg/lb], q 24 h, without food).

The objective of this investigation was to develop a systematic method for the determination of optimal processing temperatures of drug-polymer mixtures for the development of amorphous solid dispersion (ASD) by melt extrusion. Since melt extrusion is performed at high temperature, it is essential that the processing temperature should be as low as possible to minimize degradation of drug and polymer, and yet the temperature should be high enough that the drug-polymer mixture attains certain viscosity that is extrudable and the drug dissolves in the molten polymer. By using itraconazole (ITZ) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus®, BASF) as, respectively, the model drug and the polymeric carrier, melt viscosities of drug-polymer mixtures with 5, 10, 20 and 30% ITZ were studied as functions of temperature and angular frequency. All these concentrations were below the miscibility limit as it was shown separately by film casting that ITZ was miscible with the polymer up to 40%. Since the angular frequency of a rheometer may not be high enough to simulate the shear rate within an extruder, torque analysis as a function of temperature during melt extrusion of selected drug-polymer mixtures was also conducted. The presence of dissolved ITZ had a plasticizing effect on the polymer used, and an intersection point around 150-155°C was observed, above which viscosities of drug-polymer mixtures were lower than that of polymer itself. Drug-polymer mixtures with 5 to 30% ITZ were extrudable at 150°C, and torque analysis showed that the mixture with 20% ITZ can be extruded even at 145°C. These temperatures were 17 to 22°C below the melting point of ITZ (167°C). ITZ dissolved due to the drug-polymer miscibility, the viscosity attained, and the shear rate generated. It was confirmed by PXRD and DSC that the extrudates were amorphous. Viscosity and miscibility of drug-polymer mixtures during melt extrusion were identified as critical factors in determining optimal processing temperature., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: To assess therapeutic levels, safety and tolerability of a novel formulation SUBA-itraconazole (where SUBA stands for SUper BioAvailability) when compared with conventional itraconazole liquid when used as antifungal prophylaxis in patients undergoing allogeneic HSCT or in haematological malignancy patients with an intermediate/high risk of invasive fungal infection (IFI)., Methods: This was a single-institution, prospective cohort study using a historical control group as the comparator., Results: A total of 57 patients were assessed: 27 in the SUBA-itraconazole cohort and 30 in the liquid itraconazole cohort. Therapeutic concentrations were achieved significantly more quickly in the SUBA-itraconazole group: median of 6 (95% CI 5-11) days versus 14 (95% CI 12-21) days in the liquid itraconazole group (P < 0.0001). At day 10, therapeutic concentrations were achieved in 69% (95% CI 44%-81%) of the SUBA-itraconazole group versus 21% (95% CI 7%-33%) of the liquid itraconazole group (P < 0.0001). The mean trough serum concentrations at steady-state of SUBA-itraconazole were significantly higher, with less interpatient variability [1577 ng/mL, coefficient of variation (CV) 35%] versus liquid itraconazole (1218 ng/mL, CV 60%) (P < 0.001). There were two (7.4%) treatment failures in the SUBA-itraconazole group, both due to cessation of therapy for mucositis, compared with seven (23.3%) treatment failures in the liquid itraconazole group, due to subtherapeutic levels (five), mucositis (one) and gastrointestinal intolerance (one) (P = 0.096)., Conclusions: The use of the SUBA-itraconazole formulation was associated with more rapid attainment of therapeutic levels with less interpatient variability compared with conventional liquid itraconazole when used as IFI prophylaxis in allogeneic HSCT or intermediate-/high-IFI risk haematological malignancy patients., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: Solid dispersion formulations have attracted attention to improve solubility and bioavailability of water-insoluble drugs. In this study, the variation of solubility and bioavailability by different preparation methods were studied using itraconazole (ITZ) solid dispersions., Methods: Itraconazole solid dispersions were prepared by a solvent-controlled precipitation method (SCPM) using HPMCAS-LF, HCl antisolvent or a spray-drying method (SDM) for comparison. Dissolution tests by pH transition and pharmacokinetic study using male Sprague Dawley rats were conducted., Key Findings: Itraconazole solid dispersion dissolution tests by pH transition exhibited better dissolution compared to naive ITZ, limited dissolution in acidic conditions and a burst release at neutral pH. The ITZ solid dispersions by SCPM indicated a smaller-sized particle dispersion, limited dissolution at acidic pH and a higher release at neutral pH compared to those by SDM, suggesting that the increased protonation of anionic polymers and HPMCAS-LF by acidic antisolvent could form a tighter hydrophobic aggregation with ITZ in solid dispersions. ITZ solid dispersion prepared by SCPM also showed improved ITZ absorption in male Sprague Dawley rats compared to SDM and naïve ITZ., Conclusions: This study suggests that the SCPM method can be widely used for solid dispersion preparations due to improved dissolution and PK profile., (© 2017 Royal Pharmaceutical Society.)

Itraconazole is a first-generation triazole agent with an extended spectrum of activity; it is licensed in adults for superficial and systemic fungal infections; no recommendation has been yet established for use in children patients. Its variable and unpredictable oral bioavailability make it difficult to determine the optimal dosing regimen. Hence, therapeutic drug monitoring, highly available in clinical practice, may improve itraconazole treatment success and safety. The aim of the study was to describe in paediatrics the oral itraconazole pharmacokinetics, used for prophylaxis. Moreover, we evaluated the utility of its therapeutic drug monitoring in this cohort. A fully validated chromatographic method was used to quantify itraconazole concentration in plasma collected from paediatric patients, at the end of dosing interval. Associations between variables were tested using the Pearson test. Mann-Whitney U test has been used to probe the influence of categorical variables on continuous ones. Any predictive power of the considered variables was finally evaluated through univariate and multivariate linear and logistic regression analyses. A high inter-individual variability was shown; ethnicity (beta coefficient, β -0.161 and interval of confidence at 95%, IC -395.035; -62.383) and gender (β 0.123 and IC 9.590; 349.395) remained in the final linear regression model with P value of .007 and .038, respectively. This study highlights that therapeutic drug monitoring is required to achieve an adequate target itraconazole serum exposure., (© 2017 John Wiley & Sons Australia, Ltd.)

Background: Itraconazole is commonly used for treatment of systemic and cutaneous mycoses in veterinary medicine. Two formulations, capsule and solution, are used interchangeably in dogs. However, marked differences in bioavailability have been reported in other species. Similar investigations have not been performed in dogs., Objective: To determine and compare pharmacokinetics of itraconazole in dogs after oral administration of commercially available capsule and solution formulations intended for use in humans., Animals: Eight healthy, adult, purpose-bred dogs., Methods: Dogs received approximately 10 mg/kg of innovator-formulated itraconazole solution and capsule PO in randomized, crossover design with a 10-day washout period. To ensure maximal absorption, solution was administered to fasted dogs, whereas capsules were co-administered with food. Blood samples were collected at predetermined time points, and plasma drug concentrations were measured using high-pressure liquid chromatography. Pharmacokinetic parameters were determined with compartmental analysis., Results: The mean relative bioavailability of the capsule was 85% that of the solution, but drug absorption was variable, and overall drug concentrations were similar between formulations. Mean elimination half-lives of both formulations were nearly identical at approximately 33 hours. Regardless of formulation, simulations suggest that a loading dose of 20 mg/kg, followed by 10 mg/kg once every 24 hours, will result in plasma concentrations considered to be adequate in most dogs., Conclusions and Clinical Importance: Contrary to findings reported in other species, overall drug exposures after capsule and solution administration are not substantially different in dogs. Despite some pharmacokinetic differences between itraconazole capsule and solution, formulation-specific dosages do not appear to be necessary., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Chytridiomycosis is caused by the fungus Batrachochytrium dendrobatidis and is one of the primary causes of the global decline in amphibian populations and specifically of the Panamanian golden frog ( Atelopus zeteki ). Itraconazole has been demonstrated to be an effective treatment for chytridiomycosis by inhibiting cytochrome P450, a major enzyme important for the structure of B. dendrobatidis zoospores' plasma membranes. However, anecdotal reports of toxicity in this and other amphibian species have been reported at the 0.01% concentration. This study is the first to determine pharmacokinetics of 0.01% and 0.001% itraconazole in the Panamanian golden frog. Frogs were bathed 10 min, euthanized, and skin, liver, and heart were collected at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, and 36 hr. Itraconazole concentrations were measured using high performance liquid chromatography, and the minimum inhibitory concentration (MIC) of itraconazole (0.032 μg/ml) for B. dendrobatidis was used to determine whether therapeutic concentrations were attained. Itraconazole was detected in all tissues at both concentrations, indicating systemic absorption. At the 0.01% itraconazole bath, itraconazole concentrations in all tissues exceeded the MIC at all time points, and the lack of decline until the end of the study at 36 hr precluded determining a disappearance half-life. With the 0.001% bath, itraconazole exceeded the MIC and declined with a disappearance half-life that markedly varied (14.1-1,244 min). This study augments the growing literature base on chytridiomycosis and seeks to aid in further experimental attempts to find the most-optimal treatment protocol for this disease.

Background: Classic histoplasmosis is a systemic endemic mycosis due to Histoplasma capsulatum var. capsulatum. A significant reduction in the morbidity and mortality of AIDS-related histoplasmosis has been observed since the introduction of highly active antiretroviral therapy (HAART) and secondary antifungal prophylaxis., Aims: The aim of this study was to determine the current state of prognosis and treatment response of HIV-positive patients with histoplasmosis in the Francisco J. Muñiz Infectious Diseases Hospital in Buenos Aires City., Methods: A retrospective study was conducted using the demographic, clinical, immunological and treatment data of 80 patients suffering from AIDS-related histoplasmosis., Results: Of the 80 cases studied 65 were male, the median age was 36 years, with 73.7% of the patients being drug addicts, 82.5% of the patients was not receiving HAART at diagnosis, and 58.7% of the cases had less than 50 CD4+ cells/μl at the beginning of the treatment. The initial phase of treatment consisted of intravenous amphotericin B and/or oral itraconazole for 3 months, with 78.7% of the cases showing a good clinical response. Only 26/63 patients who were discharged from hospital continued with the follow-up of the HAART, secondary prophylaxis with itraconazole or amphotericin B. Secondary prophylaxis was stopped after more than one year of HAART if the patients were asymptomatic, had two CD 4 + cell counts greater than 150cells/μl, and undetectable viral loads. No relapses were observed during a two-year follow up after prophylaxis was stopped., Conclusions: The treatment of histoplasmosis in HIV-positive patients was effective in 78.8% of the cases. The combination of HAART and secondary antifungal prophylaxis is safe, well tolerated, and effective. The low adherence of patients to HAART and the lack of laboratory kits for rapid histoplasmosis diagnosis should be addressed in the future. The usefulness of primary antifungal prophylaxis for cryptococcosis and histoplasmosis HIV-positive patients should be studied., (Copyright © 2016 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.)

The oral delivery of mucoadhesive patches has been shown to enhance the absorption of large molecules such as peptides. We hypothesized that this mechanism could have utility for poorly soluble small molecules by utilizing a mucoadhesive polymer as the matrix for an amorphous solid dispersion. Binary dispersions of itraconazole and carbomer (Carbopol 71G) were prepared utilizing a thermokinetic mixing process (KinetiSol Dispersing) and the physicochemical properties were investigated by powder X-ray diffraction, calorimetry, and liquid chromatography. Adhesion of the dispersions to freshly excised porcine intestine was investigated with a texture analyzer. Minitablets were compressed from the optimal dispersion and further investigated in vitro and in vivo in rats. Thermokinetic mixing successfully processed amorphous dispersions up to 30% drug loading and each dispersion exhibited works of adhesion that were approximately an order of magnitude greater than a negative control in vitro. Ethylcellulose (EC) coated and uncoated minitablets prepared with the 30% drug load dispersion were delivered orally to rats and exhibited sustained release characteristics, with overall bioavailability greater for the uncoated minitablets compared to the EC-coated minitablets, similar to the rank order observed in our in vitro dissolution experiments. Necropsy studies showed that minitablets delivered with enteric-coated capsules targeted release to the distal small intestine and adhered to the intestinal mucosa, but the rat model presented limitations with respect to evaluating the overall performance. Based on the in vitro and in vivo results, further investigations in larger animals are a logical next step where fluid volumes, pH, and transit times are more favorable for the evaluated dosage forms., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Therapeutic drug monitoring (TDM) may be required to achieve optimal clinical outcomes in the setting of significant pharmacokinetic variability, a situation that applies to a number of anti-mould therapies. The majority of patients receiving itraconazole should routinely be managed with TDM. Voriconazole exhibits highly variable inter-individual pharmacokinetics, and a trough concentration of 1.0-5.5 mg/L is widely accepted although it is derived from relatively low-quality evidence. The case for TDM of posaconazole is currently in a state of flux following the introduction of a newer tablet formulation with improved oral bioavailability, but it may be indicated when used for either prophylaxis or treatment of established disease. The novel broad-spectrum azole drug isavuconazole does not currently appear to require TDM but 'real-world' data are awaited and TDM could be considered in selected clinical cases. For both polyene and echinocandin agents, there are insufficient data regarding the relationship between serum concentrations and therapeutic outcomes to support the routine use of TDM. A number of practical challenges to the implementation of TDM in the treatment of invasive mould infections remain unsolved. The delivery of TDM as a future standard of care will require real-time measurement of drug concentrations at the bedside and algorithms for dosage adjustment. Finally, measures of pharmacodynamic effect are required to deliver therapy that is truly individualized., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The activity of CD101 and comparator antifungal agents against 606 invasive fungal isolates collected worldwide during 2014 was evaluated using the Clinical and Laboratory Standards Institute (CLSI) method. All Candida albicans ( n = 251), Candida tropicalis ( n = 51), Candida krusei ( n = 16), and Candida dubliniensis ( n = 11) isolates were inhibited by ≤0.12 μg/ml of CD101 and were susceptible or showed wild-type susceptibility to the other echinocandins tested. Five C. glabrata isolates ( n = 100) displayed CD101 MIC values of 1 to 4 μg/ml, had elevated MICs of caspofungin (2 to >8 μg/ml), anidulafungin (2 to 4 μg/ml), and micafungin (2 to 4 μg/ml), and carried mutations on fks1 and fks2 Candida parapsilosis ( n = 92) and Candida orthopsilosis ( n = 10) displayed higher CD101 MIC values (ranges, 0.5 to 4 μg/ml and 0.12 to 2 μg/ml, respectively), and similar results were observed for the other echinocandins tested. Fluconazole resistance was noted among 11.0% of Candida glabrata isolates, 4.3% of C. parapsilosis isolates, and 2.0% of C. albicans and C. tropicalis isolates. The activity of CD101 against Aspergillus fumigatus ( n = 56) was similar to that of micafungin and 2-fold greater than that of caspofungin but less than that of anidulafungin. These isolates had wild-type susceptibility to itraconazole, voriconazole, and posaconazole. The echinocandins had limited activity against Cryptococcus neoformans ( n = 19). CD101 was as active as the other echinocandins against common fungal organisms recovered from patients with invasive fungal infections. The long half-life profile is very desirable for the prevention and treatment of serious fungal infections, especially in patients who can then be discharged from the hospital to complete antifungal therapy on an outpatient basis., (Copyright © 2017 Pfaller et al.)

Previously, modified release itraconazole in the form of a melt-extruded amorphous solid dispersion based on a pH dependent enteric polymer combined with hydrophilic additives (HME-ITZ), exhibited improved in vitro dissolution properties. These properties agreed with pharmacokinetic results in rats showing high and sustained itraconazole (ITZ) systemic levels. The objective of the present study was to better understand the best choice of rodent model for evaluating the pharmacokinetic and efficacy of this orally administered modified release ITZ dosage form against invasive Aspergillus fumigatus. A mouse model and a guinea pig model were investigated and compared to results previously published. In the mouse model, despite similar levels as previously reported values, plasma and lung levels were variable and fungal burden was not statistically different for placebo controls, HME-ITZ and Sporanox ® (ITZ oral solution). This study demonstrated that the mouse model is a poor choice for studying modified release ITZ dosage forms based on pH dependent enteric polymers due to low fluid volume available for dissolution and low intestinal pH. To the contrary, guinea pig was a suitable model to evaluate modified release ITZ dosage forms. Indeed, a significant decrease in lung fungal burden as a result of high and sustained ITZ tissue levels was measured. Sufficiently high intestinal pH and fluids available for dissolution likely facilitated the dissolution process. Despite high ITZ tissue level, the primary therapeutic agent voriconazole exhibited an even more pronounced decrease in fungal burden due to its reported higher clinical efficacy specifically against Aspergillus fumigatus.

Background: A biodegradable porous starch (BPS) was developed in order to improve dissolution and oral bioavailability of Itraconazole as a poorly water-soluble antifungal drug., Method: BPS was developed by converting native starch from hydrogel to alcogel by solvent exchange method. The developed BPS carrier was characterized by SEM and nitrogen adsorption/desorption analysis to understand surface morphology and porosity distribution respectively. Itraconazole (ITR) was loaded on BPS by adsorption mediated solvent evaporation method, which provides a hydrophilic matrix powder. This causes drug distribution within hydrophilic matrix of porous starch., Results: Solid-state characterization of optimized batch (ITR/BPS-3) was performed using DSC, PXRD, FTIR, SEM and FTIR chemical imaging. In vitro dissolution and in vivo pharmacokinetic studies were performed to evaluate therapeutic potential of ITR/BPS-3 system. In vitro studies of ITR: BPS-3 system revealed a burst effect in drug release (93%) compared to marketed product, which showed 90% drug release at the end of 60 min compared to 84% of marketed. Moreover, ITR/BPS-3 system showed improved oral bioavailability up to 3.93 fold and marketed product shows 3.12 fold compared to ITR., Conclusion: This effect is due to high surface area, improved wettability and reduced crystallinity of ITR due to its adsorption into BPS. A successful methodology was reported to prepare BPS from raw starch., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The purpose of this study was to assess the feasibility of a multicompartmental in vitro dissolution apparatus, gastrointestinal simulator (GIS), in assessing the drug dissolution of 2 commercially available oral dosage forms for itraconazole (ICZ). The GIS consists of 3 chambers, mimicking the upper gastrointestinal tract. In vitro dissolution of ICZ capsule or oral solution was evaluated in United States Pharmacopeia apparatus II and GIS. To investigate the suitability of fasted state simulated intestinal fluid (FaSSIF) to predict better in vivo, FaSSIF as well as phosphate buffer were used as dissolution media. Area under the dissolved drug amount-time curve (AUDC) was calculated for each dosage form in each apparatus, and the ratios of AUDCoral solution to AUDCcapsule were compared with human pharmacokinetic data. Based on this comparison, GIS with FaSSIF can adequately distinguish the pharmacokinetic profiles of 2 oral dosage forms for ICZ. Additionally, Caco-2 cell transepithelial transport study in combination with GIS revealed that improved drug dissolution by formulations resulted in enhanced permeation of ICZ through cell monolayer, suggesting the observed ICZ concentration in the GIS will directly reflect systemic exposure. These results indicate GIS would be a powerful tool to assess the formulations of ICZ as well as other Biopharmaceutics Classification System class II drug formulations., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Poly(glycolic acid) microneedle arrays were fabricated using a drawing lithography process; these arrays were modified with a drug release agent and an antifungal agent by piezoelectric inkjet printing. Coatings containing poly(methyl vinyl ether-co-maleic anhydride), a water-soluble drug release layer, and itraconazole (an antifungal agent), were applied to the microneedles by piezoelectric inkjet printing. Microscopic evaluation of the microneedles indicated that the modified microneedles contained the piezoelectric inkjet printing-deposited agents and that the surface coatings were released in porcine skin. Energy dispersive x-ray spectrometry aided in confirmation that the piezoelectric inkjet printing-deposited agents were successfully applied to the desired target areas of the microneedle surface. Fourier transform infrared spectroscopy was used to confirm the presence of the component materials in the piezoelectric inkjet printing-deposited material. Itraconazole-modified microneedle arrays incubated with agar plates containing Candida albicans cultures showed zones of growth inhibition.

The current available formulations of itraconazole are not ideal for dosing in cats. The capsular preparation often does not allow for accurate dosing, the oral solution is difficult to administer and poorly tolerated, and the bioavailability of compounded formulations has been shown to be poor in other species. The aim of this study was to evaluate every other day dosing of 100 mg itraconazole capsule in healthy adult cats. Ten healthy adult cats received a 100 mg capsule of itraconazole orally every 48 h for 8 weeks. Peak and trough serum concentrations of itraconazole were measured weekly using high-performance liquid chromatography (HPLC). Physical examination, complete blood count (CBC), and chemistry profiles were performed weekly. The dosage regimen achieved average therapeutic trough concentrations (>0.5 μg/mL) within 3 weeks. The protocol yielded no adverse effects in 8 of the 10 study cats, with affected cats recovering fully with discontinuation of the drug and supportive care. At 8 weeks, an average peak concentration of 1.79 ± 0.952 μg/mL (95% CI: 0.996-2.588) and an average trough concentration of 0.761 ± 0.540 μg/mL (95% CI: 0.314-1.216) were achieved. Overall, a 100 mg every other day oral dosage regimen for itraconazole in cats yielded serum concentrations with minimal fluctuation and with careful monitoring may be considered for treatment of cats with systemic fungal disease., (© 2015 John Wiley & Sons Ltd.)

Ketoconazole has been widely used as a strong cytochrome P450 (CYP) 3A (CYP3A) inhibitor in drug-drug interaction (DDI) studies. However, the US Food and Drug Administration has recommended limiting the use of ketoconazole to cases in which no alternative therapies exist, and the European Medicines Agency has recommended the suspension of its marketing authorizations because of the potential for serious safety concerns. In this review, the Innovation and Quality in Pharmaceutical Development's Clinical Pharmacology Leadership Group (CPLG) provides a compelling rationale for the use of itraconazole as a replacement for ketoconazole in clinical DDI studies and provides recommendations on the best practices for the use of itraconazole in such studies. Various factors considered in the recommendations include the choice of itraconazole dosage form, administration in the fasted or fed state, the dose and duration of itraconazole administration, the timing of substrate and itraconazole coadministration, and measurement of itraconazole and metabolite plasma concentrations, among others. The CPLG's recommendations are based on careful review of available literature and internal industry experiences., (© 2015, The American College of Clinical Pharmacology.)

Background and Objectives: Empirical antifungal therapy prevents invasive fungal infections in patients with cancer. This study assessed the empirical efficacy of intravenous itraconazole in pediatric patients undergoing hematopoietic stem cell transplantation, and investigated the pharmacokinetics and clinical implications., Methods: Oral itraconazole syrup was started (2.5 mg/kg twice daily) for prophylaxis, and patients with persistent neutropenic fever for more than 2 days were switched to intravenous itraconazole (5 mg/kg twice daily for 2 days for induction and 5 mg/kg daily for maintenance) as empirical treatment. Empirical antifungal efficacy was assessed retrospectively in 159 transplantations, and a full pharmacokinetic study was prospectively conducted in six of these patients. Successful antifungal efficacy was defined as the fulfillment of all components of a five-part composite end point., Results: The overall empirical antifungal success rate fulfilling all criteria was 42.1 %. No death or drug-related serious adverse events occurred during the study. Mean trough plasma concentration of itraconazole after oral prophylaxis and intravenous induction were 577.2 and 1659.7 μg/L, respectively. Mean area under the concentration-time curve of itraconazole and its metabolite at steady state were 42,837 ± 24,746 μg·h/L and 63,094 ± 19,255 μg·h/L., Conclusions: Intravenous itraconazole was effective and safe as an empirical antifungal agent in pediatric patients; this was due to the fast and satisfactory increase in drug concentration by switching from oral to intravenous therapy.

Spray drying experiments of an itraconazole nanosuspension were conducted to generate a dry nanocrystal powder which was subsequently formulated into a tablet formulation for direct compression. The nanosuspension was prepared by high pressure homogenization and characterized for particle-size distribution and surface morphology. A central composite statistical design approach was applied to identify the optimal drug-to-excipient ratio and spray drying temperature. It was demonstrated that the spray drying of a nanosuspension with a mannitol-to-drug mass ratio of 4.5 and at an inlet temperature of 120 °C resulted in a dry powder with the smallest increase in particle size as compared with that of the nanosuspension. X-ray diffraction results indicated that the crystalline structure of the drug was not altered during the spray-drying process. The tablet formulation was identified by determining the micromeritic properties such as flowability and compressibility of the powder mixtures composed of the spray dried nanocrystal powder and other commonly used direct compression excipients. The dissolution rate of the nanocrystal tablets was significantly enhanced and was found to be comparable to that of the marketed Sporanox®. No statistically significant difference in oral absorption between the nanocrystal tablets and Sporanox® capsules was found. In conclusion, the nanosuspension approach is feasible to improve the oral absorption of a BCS Class II drug in a tablet formulation and capable of achieving oral bioavailability equivalent to other well established oral absorption enhancement method.

The purpose of this study was to investigate the feasibility of entrapping water-insoluble drug itraconazole into solid lipid nanoparticles (SLNs) for topical ocular delivery. The drug-loaded SLNs were prepared from stearic acid and palmitic acid using different concentrations of polyvinyl alcohol employed as emulsifier. SLNs were prepared by the melt-emulsion sonication and low temperature-solidification method and characterized for particle size, zeta potential, drug loading and drug entrapment efficiency. The mean particle size of SLNs prepared with stearic acid ranged from 139 to 199 nm, while the SLNs prepared with palmitic acid had particle size in the range of 126-160 nm. The SLNs were spherical in shape. Stearic acid-SLNs showed higher entrapment of drug compared with palmitic acid-SLNs. Differential scanning calorimetry (DSC) and X-ray diffraction measurements showed decrease in crystallinity of drug in the SLN formulations. The modified Franz-diffusion cell and freshly excised goat corneas were used to test drug corneal permeability. Permeation of itraconazole from stearic acid-SLNs was higher than that obtained with palmitic acid-SLNs. The SLNs showed clear zone of inhibition against Aspergillus flavus indicating antimicrobial efficacy of formulations.