Plasma Concentrations Of Itraconazole Research Articles

Plasma itraconazole concentrations during treatment of feline sporotrichosis.

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 (100mg/cat/day) or combination therapy with ITZ (100mg/cat/day) and KI (2.5-5mg/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 4h 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 0.75µg/mL. The median plasma ITZ concentration was 0.5µg/mL in cats that received ITZ monotherapy (n=12) and 1.0µg/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 (>0.5µg/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.

Effect of Itraconazole and Its Metabolite Hydroxyitraconazole on the Blood Concentrations of Cyclosporine and Tacrolimus in Lung Transplant Recipients.

Invasive Aspergillus infection is a major factor for poor prognosis in patients receiving lung transplantation (LT). An antifungal agent, itraconazole (ITCZ), that has antimicrobial activity against Aspergillus species, is used as a prophylactic agent against Aspergillus infection after LT. ITCZ and its metabolite, hydroxyitraconazole (OH-ITCZ), potently inhibit CYP3A and P-glycoprotein that metabolize or excrete calcineurin inhibitors (CNIs), which are the first-line immunosuppressants used after LT; thus, concomitant use of ITCZ and CNIs could induce an increase in the blood concentration of CNIs. However, no criteria for dose reduction of CNIs upon concomitant use with ITCZ in LT recipients have been defined. In this study, the effect of ITCZ and OH-ITCZ on the blood concentrations of two CNIs, tacrolimus and cyclosporine, after LT were retrospectively evaluated. A total of 39 patients who received LT were evaluated. Effects of ITCZ and OH-ITCZ on the concentration/dosage (C/D) ratio of tacrolimus and cyclosporine were analyzed using linear mixed-effects models. The plasma concentrations of OH-ITCZ were about 2.5-fold higher than those of ITCZ. Moreover, there was a significant correlation between the plasma concentrations of ITCZ and OH-ITCZ. Based on parameters obtained in the linear regression analysis, the C/D ratios of cyclosporine and tacrolimus increase by an average of 2.25- and 2.70-fold, respectively, when the total plasma concentration of ITCZ plus OH-ITCZ is 1000 ng/mL. In conclusion, the plasma levels of ITCZ and OH-ITCZ could be key factors in drawing up the criterion for dose reduction of CNIs.

Plasma concentrations of itraconazole following a single oral dose in juvenile California sea lions (Zalophus californianus).

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 5-10mg/kg. Blood samples were collected from each animal at 0hr and attwo of the following timepoints: 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72hr. Quantitative analysis of itraconazole in plasma samples was performed by high-performance liquid chromatography. An average maximum concentration of 0.22µg/ml±0.11 was detected 4hr after administration. The average concentration fell to 0.12µg/ml±0.11 by 6hr and 0.02µg/ml±0.02 at 12hr. At no point did concentrations reach 0.5µg/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 5-10mg/kg, under the conditions used in this study, does not achieve therapeutic plasma concentrations in California sea lions.

Effective plasma concentrations of itraconazole and its active metabolite for the treatment of pulmonary aspergillosis

BackgroundItraconazole (ITCZ) is used to treat pulmonary aspergillosis, but findings regarding the range of effective plasma concentrations are often contradictory. This study attempted to determine effective plasma concentrations of ITCZ and its active metabolite hydroxyitraconazole (OH-ITCZ) by retrospectively analyzing their relationships to clinical efficacy. MethodsThe study included 34 patients with pulmonary aspergillosis treated using ITCZ (mean age, 70 years). Each patient was treated with 200 mg ITCZ once daily (mean duration of treatment: 384 days). Plasma concentrations of ITCZ and OH-ITCZ at trough levels from 7 to 889 days after the start of treatment were determined using high-performance liquid chromatography. Clinical efficacy was assessed through the improvement clinical symptoms. ResultsFifteen patients were classified as effective group and the other 19 patients as non-effective group. Mean (±standard deviation) ITCZ trough plasma concentration was significantly higher in effective group (1254 ± 924 ng/mL) than in non-effective group (260 ± 296 ng/mL). Mean OH-ITCZ plasma concentration was significantly higher in effective group (1830 ± 1031 ng/mL) than in non-effective group (530 ± 592 ng/mL). Receiver operating characteristic curve analysis revealed the optimal cutoff for ITCZ trough plasma concentration was 517 ng/mL, and 86.7% of effective group showed concentrations exceeding this value. The optimal cutoff for total ITCZ + OH-ITCZ plasma concentration was 1025 ng/mL, and 93.3% of effective group showed a concentration exceeding this value. ConclusionsOur findings indicate that effective plasma concentration ranges for the treatment of pulmonary aspergillosis begin at an ITCZ trough plasma concentration of 500 ng/mL and a total ITCZ + OH-ITCZ plasma concentration of 1000 ng/mL.

Abstract CT087: Concentration-dependent early anti-vascular and anti-tumor effects of itraconazole in non-small cell lung cancer (NSCLC)

Abstract Introduction: Itraconazole has been repurposed as an anti-cancer therapeutic agent for multiple malignancies, including prostate cancer, and basal cell carcinoma, and lung cancer. In preclinical models, itraconazole has antiangiogenic properties and reduces Hedgehog (Hh) pathway activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients. Methods: Patients who had NSCLC planned for surgical resection were administered 10-14 days of itraconazole 300 mg orally twice daily. Prior to and at the end of therapy, patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic (PK) and pharmacodynamic analyses. Tissue from pre-treatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyl-itraconazole concentration, as well as vascular and Hh pathway biomarkers. Results: A total of 13 patients were enrolled, of whom 8 completed the course of itraconazole and all biomarker studies. Itraconazole was generally well tolerated. Steady state plasma concentrations of itraconazole and hydroxyl-itraconazole demonstrated low intra-patient variability, but there was a six-fold difference in AUC (area under contrast curve) between patients. Itraconazole treatment did not alter transcription of GLI1 (P=0.20) and PTCH1 (P=0.34) mRNA in skin biopsies. There was a significant association between itraconazole PK and (a) tumor volume reduction (Spearman rank correlation -0.71; P=0.05), and (b) tumor perfusion (Ktrans) (correlation -0.71; P=0.01). Changes in IL-1b, G-CSF, and GM-CSF concentrations were significantly correlated with tumor volume reduction. Conclusions: Itraconazole demonstrates exposure-dependent early anti-vascular and anti-tumor effects in patients with NSCLC. However, it appears to have little activity against the Hh pathway. As interest in vascular-directed therapies re-emerges in this disease, itraconazole may offer a relatively inexpensive, convenient, and well-tolerated option. Funding: Department of Defense (DOD) W81XWH-13-LCRP-CEA Lung Cancer Research Program Clinical Exploration Award Citation Format: David E. Gerber, Farjana J. Fattah, Rolf A. Brekken, Rachael Skelton, Jessica Saltarski, Chul Ahn, Kemp H. Kernstine, Chyndhri Padmanabhan, Vaidehi Chemburkar, Sahba Kasiri, Rajareddy Kallem, Indhumathy Subramaniyan, Qing Yuan, Quyen N. Do, Yin Xi, Ivan Pedrosa, William C. Putnam, James Kim. Concentration-dependent early anti-vascular and anti-tumor effects of itraconazole in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT087.

Optimization of Individual Pharmacotherapy Based on Multiple Evaluations of Patient Data

To date, limited drug information is available for the individual optimization of pharmacotherapy. The author attempted multiple evaluations of patient data on factors related to the pharmacokinetics, drug efficacy, and adverse reactions observed in clinical settings. Through the clinical studies, drug information on the individual optimization of pharmacotherapy needed by health professionals including physicians and pharmacists was identified. Major findings were: 1) Cachectic cancer patients had high plasma concentrations of oxycodone via the reduction of CYP3A activity. The metabolic reduction in cachectic cancer patients was potentially related to the elevated serum level of interleukin-6. 2) Dopamine receptor D2 (DRD2) genetic mutations and being female led to poor antiemetic efficacy of the treatment of opioid-induced nausea in prochlorperazine-treated patients. The opioid receptor μ1 (OPRM1) wild genotype in addition to being female and having high plasma concentrations of prochlorperazine increased prolactin secretion during oxycodone treatment. 3) Rheumatoid arthritis patients with a genetic mutation of ATP-binding cassette subfamily B member 1 (ABCB1) had high plasma concentrations of tacrolimus and its 13-O-demethylate. The ABCB1 genetic mutation and associated high plasma concentration of tacrolimus decreased kidney function. 4) Chronic inflammation increased the plasma voriconazole concentration via its poor metabolism, whereas it did not alter the plasma itraconazole concentration. Although co-administration of prednisolone did not affect the plasma concentration of triazole antifungals, it weakly increased voriconazole metabolism. 5) In breastfeeding women, the median milk/plasma concentration ratio of amlodipine was 0.85. However, the observed relative infant dose of amlodipine in most patients was less than 10%.

Bioequivalence study of two formulations of itraconazole 100 mg capsules in healthy volunteers under fed conditions: a randomized, three-period, reference-replicated, crossover study

ABSTRACTBackground: 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 AUC0-72h, AUC0-∝, Cmax, Tmax, T1/2 and Kel.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 AUC0-72h. Since the coefficient of variation (CV) for the reference product was 44.95% for Cmax, 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.

Plasma Concentration of Itraconazole in Patients With Hematologic Malignancies Treated With Itraconazole Oral Solution.

The prophylactic administration of itraconazole (ITCZ) is effective for preventing mycotic infections during chemotherapy in patients with hematologic malignancies. However, fungal infections can occur when the ITCZ does not reach an effective concentration. We conducted a prospective study to monitor the plasma concentration of ITCZ and hydroxyl-ITCZ (OH-ITCZ) weekly and to verify whether the day 3 plasma concentration of ITCZ could predict the subsequent acquisition of an effective plasma concentration. A total of 39 patients who underwent 66 courses of chemotherapy were assessed in this study. An effective plasma concentration was achieved on day 7 in 34 of 63 patients (54%) and on day 14 in 35 of 59 patients (59%). A univariate analysis revealed that age, type of chemotherapy, and the body surface area were significantly associated with a high plasma concentration of ITCZ + OH-ITCZ. A linear regression analysis extracted the body surface area and the type of chemotherapy as significant factors. An receiver operating characteristic curve analysis revealed a day 3 plasma ITCZ + OH-ITCZ concentration of >656 ng/mL led to a plasma concentration that exceeded the minimum effective level on day 7; the sensitivity and specificity were 62% and 93%, respectively. This study showed that the measurement of the day 3 plasma concentration could lead to a better outcome in patients receiving chemotherapy for hematologic malignancies.

Plasma Concentrations of Itraconazole, Voriconazole, and Terbinafine When Delivered by an Impregnated, Subcutaneous Implant in Japanese Quail (Coturnix japonica)

Aspergillosis is a common fungal infection in both wild and pet birds. Although effective antifungal medications are available, treatment of aspergillosis can require months of medication administration, which entails stressful handling one or more times per day. This study examined the delivery of the antifungal drugs itraconazole, voriconazole, and terbinafine to Japanese quail ( Coturnix japonica ) via an impregnated implant. Implants contained 0.5, 3, 8, or 24 mg of itraconazole, voriconazole, or terbinafine. The implants were administered subcutaneously over the dorsum and between the scapulae. Blood was collected from birds before and 2, 7, 21, 42, and 56 days after implant placement. Plasma was analyzed by high-performance liquid chromatography for concentrations of itraconazole, voriconazole, or terbinafine, as appropriate. During the course of the study, targeted terbinafine concentrations were achieved in some birds at various time points, but concentrations were inconsistent. Itraconazole and voriconazole concentrations were also inconsistent and did not reach targeted concentrations. Currently, the implant examined in this study cannot be recommended for treatment of aspergillosis in avian species.

Successful empirical antifungal therapy of intravenous itraconazole with pharmacokinetic evidence in pediatric cancer patients undergoing hematopoietic stem cell transplantation.

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. 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. 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. 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.

Impact of inflammation and concomitant glucocorticoid administration on plasma concentration of triazole antifungals in immunocompromised patients

BackgroundThe expression of hepatic CYP3A decreases with inflammatory response but increases with glucocorticoid administration. The aim of this study was to evaluate the plasma concentration of voriconazole and itraconazole under inflammatory conditions and glucocorticoid therapy. MethodsForty-one voriconazole- and 42 itraconazole-treated immunocompromised patients were enrolled in this study. Plasma concentrations of triazoles and their major metabolites at 12h after dosing were determined. The relationships between C-reactive protein (CRP), prednisolone dose, and plasma exposure parameters of triazole were evaluated. ResultsPlasma concentration of voriconazole was not correlated with that of its N-oxide. A higher CRP was correlated with a higher dose-normalized plasma concentration of voriconazole and a lower plasma concentration ratio of N-oxide to voriconazole. Prednisolone dose was weakly correlated with the plasma concentration ratio of N-oxide to voriconazole. Plasma concentration of itraconazole had a good correlation with that of its hydroxide. Parameters of itraconazole were not associated with CRP and prednisolone dose. ConclusionsAn inflammatory state raised the plasma concentration of voriconazole through its metabolic reduction, while it did not have an effect on plasma concentration of itraconazole. Concomitant glucocorticoid administration slightly elevated the voriconazole metabolism, although it did not affect the plasma concentration of triazoles.

Antifungal Use and Therapeutic Monitoring of Plasma Concentrations of Itraconazole in Heart and Lung Transplantation Patients

The prophylactic use of itraconazole has dramatically reduced the incidence of fungal infections in patients after solid-organ transplantation. To further reduce this incidence, it has been suggested that plasma concentrations of itraconazole be monitored and maintained above a putative minimum target concentration of 500 ng/mL. A retrospective audit was undertaken of patients who had had a heart or lung transplant over a 14-month period (between January 1, 2010 and March 31, 2011). The itraconazole prophylaxis regimen (dose, time of last dose, time of blood collection) and plasma concentrations were recorded together with the use of concomitant antacid medication. Details of breakthrough fungal infections were documented. Eighty-four heart or lung organ transplantations were undertaken in the study period; 57 were treated prophylactically with itraconazole. Plasma concentrations of itraconazole were monitored in 56% (n = 32) of these cases. Considerable interpatient (range, 50-2000 ng/mL) and intrapatient variability in plasma concentrations was observed. The putative target was not achieved consistently in the majority of cases. All patients were taking a proton pump inhibitor. Six of the cohort developed an invasive fungal infection. None of the 3 patients for whom plasma concentrations were monitored was above the target concentration. Further clinical studies, involving monitoring of the active metabolite and attention to the importance of the stereoisomers of itraconazole, may give better insight into the appropriateness of the currently suggested minimum target concentration, whose validity remains uncertain. Formulations with improved absorption characteristics could reduce the variability of absorption with the goal of further reducing the incidence of infrequent, but life-threatening, invasive fungal infections.

Successful Empirical Antifungal Therapy of Intravenous Itraconazole with Pharmacokinetic Evidence in Pediatric Cancer Patients Undergoing Hematopoietic Stem Cell Transplantation

Abstract 3019▪FN2▪This icon denotes a clinically relevant abstract Introduction:Itraconazole is a widely used antifungal agent with a broad spectrum of activity, but pharmacokinetics has large inter- and intra-individual variability. The optimal usages of itraconazole from numerous pharmacokinetic studies have been proposed in adults. However, application of itraconazole in pediatric patients is limited since its pharmacokinetics in children is less known. This study assessed the efficacy of the empirical use of intravenous (IV) itraconazole in pediatric patients undergoing hematopoietic stem cell transplantation and investigated the pharmacokinetics of repeated-doses of itraconazole and its active metabolite hydroxyitraconazole. Patients & Methods:Efficacy was evaluated in 85 patients undergoing hematopoietic stem cell transplantation (32 allogeneic, 53 autologous). Oral itraconazole prophylaxis (2.5 mg/kg twice daily) was started on the day -2 of the conditioning chemotherapy. Itraconazole was changed to IV form in patients with persistent neutropenic fever over 2 days (5 mg/kg twice daily for 2 days for induction and 5 mg/kg daily for maintenance). Itraconazole was continued until the absolute neutrophil count was over 1, 000/uL, the development of fungal disease, the development of unacceptable drug toxicity or death, or the withdrawal from study. Empirical treatment was considered successful if all of the following criteria were met: successful treatment of baseline fungal infection, absence of breakthrough fungal infection, survival for 7 days after therapy, resolution of neutropenic fever, and no premature discontinuation due to toxicity or lack of efficacy. Full pharmacokinetic study was conducted in 6 patients (1 allogeneic, 5 autologous). For pharmacokinetic study, trough level during oral itraconazole was measured with blood collected before the 5th dose. Blood for trough level of IV administrations were sampled prior to every induction doses and 1–5th IV maintenance doses. For area under the plasma concentration-time curve (AUC) analysis, serial blood samples were collected prior to the 3rd IV maintenance infusion, and 1, 2, 4, 8, 12, 24hr after the infusion. Plasma concentrations of itraconazole and hydroxyitraconazole were determined using a validated HPLC method. Results:The overall success rates fulfilling all criteria were 32.9%. There was no patient with baseline fungal infection, but 1 patient with breakthrough fungal infection, and all patients were survived for 7 days after discontinuation of itraconazole. The rates of resolution of fever in 48 hours after itraconazole were 32.9%, and premature discontinuation occurred in 23.5% of patients. The causes of discontinuation were persistent fever in 17 (20%) patients, and nausea or vomiting in 3 (3.5%) patients. There was no Grade 3–4 toxicity associated with itraconazole.The mean trough plasma concentration of itraconazole after oral prophylaxis and intravenous induction were 577.2 and 1413.3 ng/ml. The median pharmacokinetic values for steady-state itraconazole and hydroxyitraconazole, respectively, were as follows: AUC form 0 to 24 h (AUC24), 42.8 and 63.1 μg · h/ml; clearance (CL) at steady state, 63.5 and 38.5 ml/min; and volume of distribution at steady state (Vdss), 201.8 and 711.2 L. According to the results, sufficient trough level was achieved during oral prophylaxis, and levels were rising rapidly by successive IV inductions so that the steady concentration of twice the level of oral itraconazole was maintained during IV maintenance with this empirical strategy.Compared with a previous pediatric single intravenous study, lower CL for itraconazole and metabolite were observed, which can be explained by saturable drug metabolism with multiple dosing, as found in adults. Dose adjusted steady state AUC24 of itraconazole and metabolite were about twice of those in the adults, and relatively smaller clearance of study drug needs to be considered for pediatric use. Conclusion:IV itraconazole was effective and safe as an empirical antifungal agent in pediatric patients undergoing hematopoietic stem cell transplantation, and this is considered to be due to the fast and satisfactory increase in the drug concentration by switching oral prophylaxis to IV itraconazole. There are considerable pharmacokinetic differences between children and adults with respect to itraconazole and its active metabolite, which should be considered with pediatric usages. Disclosures:No relevant conflicts of interest to declare.

Rikkunshi-to Partially Reverses Cancer Chemotherapy-Induced Decrease in Plasma Valproic Acid Concentration in a Patient with Malignant Lymphoma

A fifty-five-year-old male patient with malignant lymphoma who took oral valproic acid (VPA) tablets and itraconazole (ITZ) capsles received 3 courses of cancer chemotherapy, including 2 courses of a combination of rituximab/methotrexate/ifosphamide/etoposide/ carboplatin/ methylpredonisolon (R-IMVP16/CBDCA regimen) and subsequent one course of a combination of rituximab/ranimustine/citara bine/etoposide/merphalan (R-MEAM regimen). Plasma concentration of VPA dramatically decreased below the therapeutic concentration after the first and second chemotherapy and seizures appeared in both cases. Plasma concentration of ITZ was also lowered after the second chemotherapy course. At the third chemotherapy, Rikkunshi-to, a Japanese herbal medicine, was prescribed for 14 days. Plasma VPA concentration decreased, though to a lesser extent, after chemotherapy, in which the level was near the border of therapeutic concentration. No convulsion was observed. Therefore, care should be taken to monitor plasma drug concentration during cancer chemotherapy. Rikkunshi-to may be useful to alleviate the chemotherapy-induced decrease in plasma concentrations of orally administered drugs.

慢性肺アスペルギルス症に対するイトラコナゾール注射薬と 高用量カプセル薬による維持療法の検討

Itraconazole (ITCZ) is a novel triazole antifungal with a broad spectrum including Aspergillus species. We conducted a three-month open, noncomparative multicenter study of the efficacy and safety of ITCZ injections and high dose capsules in chronic pulmonary aspergillosis. Patients with chronic pulmonary aspergillosis received intravenous injection of ITCZ (200mg) (twice a day for the first two days, then once a day for the following 3-12 days) prior to the oral administration of ITCZ capsules (200mg) twice a day. Radiologic findings by chest CT and clinical symptoms were evaluated at baseline and 12 weeks later. We also measured ITCZ plasma trough concentrations after two weeks and four weeks of the study. Twenty patients were included in the study, among which 14 patients presented with chronic necrotizing pulmonary aspergillosis (CNPA) and 6 presented with pulmonary aspergilloma. The efficacy evaluation was available in 17 patients (CNPA, 12 patients; aspergilloma, 5 patients). Radiological improvement was observed in nine (52.9%, 95%CI: 31.0%-73.8%) patients (CNPA, 7 patients; aspergilloma, 2 patients). One patient with aspergilloma showed deterioration. The clinical symptoms showed significant improvement on expectoration, bloody sputum, and pyrexia. Two patients had to stop treatment with ITCZ because of congestive heart failure. Other adverse effects were reported but did not lead to the discontinuation of treatment, as follows: hepatic dysfunction, two patients; hypokalemia, nine patients. In two patients who combined pulmonary Mycobacterium avium complex disease coadministration of ITCZ and rifampicin was done. Their ITCZ plasma concentrations were extremely low, and one of them was the only deterioration case in the primarily radiologic evaluation. Itraconazole injections and high dose capsules maintenance therapy is effective in treating chronic pulmonary aspergillosis.

Effects of Compounding on Pharmacokinetics of Itraconazole in Black-Footed Penguins (Spheniscus demersus)

Itraconazole is used to treat and prevent aspergillosis in captive penguin colonies. Although commercial formulations of itraconazole are available, compounding is sometimes performed to decrease cost or to provide a different concentration of the drug. Using a two-way crossover design, the pharmacokinetics of both a commercially available oral itraconazole solution and a compounded oral itraconazole solution were compared in six black-footed penguins (Spheniscus demersus). Each itraconazole formulation was administered orally in frozen-thawed capelin at 7 mg/kg. Plasma itraconazole concentrations at time 0 (pretreatment), 20 and 40 min post-drug administration, and 1, 2, 4, 6, 8, and 12 hr post-drug administration were determined using reverse-phase high-performance liquid chromatography. Drug concentrations were analyzed using standard pharmacokinetic methods. Plasma clearance of the commercial itraconazole solution was more rapid than the clearance published for other species, possibly warranting more frequent dosing in black-footed penguins. Absorption of itraconazole, as determined by peak concentration and area under the curve, was significantly higher for the commercial formulation when compared to the compounded formulation, likely as a result of the presence of cyclodextrin, a carrier compound shown to improve oral absorption, in the commercial formulation. Extrapolating dosing regimens for compounded itraconazole formulations from regimens determined for commercial formulations warrants caution as a result of the significant differences in pharmacokinetics.

A simple, sensitive high-performance liquid chromatography -ultraviolet method for the quantification of concentration and steady-state pharmacokinetics of itraconazole and hydroxyitraconazole

A steady-state trough plasma itraconazole concentration greater than 500 ng/mL is a therapeutic target for itraconazole. A simple, rapid and sensitive high-performance liquid chromatography-based method was developed for quantitation of itraconazole and hydroxyitraconazole in human plasma. Itraconazole and hydroxyitraconazole were separated using a mobile phase of 0.5% KH2PO4 (pH 6.0)-acetonitrile (30:70, v/v) on a CAPCELLPAK C18 MGII column at a flow rate of 0.5 mL/min and ultraviolet absorbance at 260 nm. The analysis required 200 microL of plasma and involved a rapid, simple solid-phase extraction with an Oasis HLB cartridge, which resulted in recoveries of 87-92% for itraconazole and 91-94% for hydroxyitraconazole. The lower limit of quantification for itraconazole and hydroxyitraconazole was 5 ng/mL each. Intra- and interday coefficients of variation for itraconazole and hydroxyitraconazole were less than 11.3% and 12.2%, respectively, and accuracies were within 11.7% and 4.5% over the linear range, respectively. Although the steady-state plasma concentrations of itraconazole and hydroxyitraconazole ranged from 506 to 2482 ng/mL and from 766 to 2444 ng/mL, respectively, after a two-day loading dose of 400 mg/day intravenous itraconazole followed by the administration of 200 mg/day itraconazole oral solution, calibration curves of itraconazole and hydroxyitraconazole showed positive linearity in a concentration range of 5-2500 and 50-2500 ng/mL, respectively. Our results indicate that this method is applicable for the monitoring of plasma levels of itraconazole and hydroxyitraconazole in a clinical setting. Furthermore, the regimen presented here might also be effective in preventing infection, but further studies with large sample sizes are necessary to investigate this avenue.

Semi-Mechanistic Population Pharmacokinetic Drug-Drug Interaction Modelling of a Long Half-Life Substrate and Itraconazole

For compounds with a long elimination half-life, the evaluation of a drug-drug interaction (DDI) study can be challenging. The standard analytical approach of a non-compartmental analysis (NCA) might not be able to detect the full interaction potential and may lead to a significant underestimation of the interaction. The most appropriate method for data analysis might be a semi-mechanistic population pharmacokinetic modelling approach. To accomplish a semi-mechanistic DDI model for a long-elimination-half-life drug substrate, tesofensine, and the cytochrome P450 (CYP) 3A4 inhibitor itraconazole, and to compare the results of the semi-mechanistic model with the results obtained from the standard NCA approach. Additionally, the impact of different schedules of itraconazole on tesofensine pharmacokinetics and the general performance of the standard NCA approach were evaluated. Overall, 28 subjects received a single oral dose of tesofensine 2 mg; 14 of these subjects were coadministered an oral itraconazole 400 mg loading dose and a 200 mg maintenance dose for 6 days before and 5 days after administration of tesofensine. The dataset contained 465 plasma concentrations of tesofensine (full profiles) and 80 plasma concentrations of itraconazole (trough values). First, pharmacokinetic models of itraconazole and tesofensine were developed in parallel. Subsequently, a combined model was developed, taking into account CYP3A4 inhibition. The analyses were performed using NONMEM software. The plasma concentration-time profiles of itraconazole and tesofensine were best described by a one-compartment model for each drug, with first-order elimination rate constants that were both inhibited by itraconazole concentrations. Inhibition resulted in reduced clearances and prolonged elimination half-lives for tesofensine and itraconazole: using NCA, the actual study revealed an approximately 9% increase in exposure for the timeframe of the coadministration with itraconazole (the area under the plasma concentration-time curve (AUC) from 0 to 144 hours [AUC(144h)]), and the impact on exposure estimated to infinity (AUC(infinity)) was approximately 26%. These results are in contrast to the model-predicted results, where the inhibitory effect of itraconazole caused a 38% reduction in the clearance of tesofensine, leading to a 63% increased exposure. This analysis presents a semi-mechanistic population pharmacokinetic approach that may be useful for the evaluation of DDI studies. The model can be an aid in evaluating DDI studies for compounds with a long elimination half-life, especially when the inhibitor cannot be administered over a sufficient period. Additionally, the population model-based approach may allow simplification of the design and the analysis and interpretation of safety and efficacy findings in DDI studies.

Development of a binary lipid nanoparticles formulation of itraconazole for parenteral administration and controlled release

The principal aim of this study was to develop an intravenous formulation of itraconazole (ITZ) using lipid nanoparticles based on binary mixture of liquid and solid lipids. Lipid nanoparticles were developed to provide the controlled release of ITZ as well as to improve the solubility of ITZ. Lipid nanoparticles were prepared with tristearin as a solid lipid, triolein as a liquid lipid, and a surfactant mixture of eggPC, Tween 80 and DSPE-PEG 2000. ITZ was incorporated at the concentration of 20 mg/g. Lipid nanoparticles were manufactured by high-pressure homogenization method. The particle size and polydispersity index (PI) of lipid nanoparticles were below 280 nm and 0.2, respectively. Zeta potentials and incorporation efficiencies of lipid nanoparticles were around −30 mV and above 80%, respectively. Lipid nanoparticles containing 1% of liquid lipid showed the smallest particles size and the highest incorporation efficiency. Results from SEM, DSC and PXRD revealed that ITZ in lipid nanoparticles exists in an amorphous state. Release rates were increased as the amount of liquid lipid in lipid core increased, demonstrating that the release of ITZ from lipid nanoparticles could be controlled by modulation of the amount of liquid lipid in lipid core. Pharmacokinetic studies were performed after intravenous administration of lipid nanoparticles in rats at the dose of 5 mg/kg. The plasma concentration of ITZ was prolonged after intravenous administration of lipid nanoparticles. It is concluded that binary lipid nanoparticles could control the release and pharmacokinetic parameters of ITZ.

Evaluation of Oral Itraconazole Administration in Captive Humboldt Penguins (Spheniscus humboldti)

Aspergillus spp. fungal infections are the most common cause of morbidity and mortality in captive penguins. Itraconazole has been the drug of choice for both therapeutic and prophylactic treatment; however, the pharmacokinetic and pharmacodynamic parameters can be highly variable in different species, and it has not been evaluated in penguins. In this study, four preliminary steady-state trials were performed to compare two oral formulations of itraconazole (commercial capsules compared with generic bulk compounded powder) at two different dosages (6 or 12 mg/kg once a day) administered in fish to small groups of captive Humboldt penguins (Spheniscus humboldti). Building on this data, a final steady-state trial was performed with the use of a 7 mg/kg oral dosage twice a day of commercial capsules given in fish to a group of 15 penguins. With sparse sampling, blood was drawn for testing from small subsets of each treatment group at 4-7 time points in the 24-hr period after the final dose of itraconazole on day 14. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole, the major metabolite, were determined by reverse phase high-performance liquid chromatography with fluorescence detection. Treatment with the generic bulk compounded product resulted in plasma levels of itraconazole that were undetectable for 26 out of 30 blood samples, compared with seven out of 20 blood samples for the commercial product at the same dosage. On the basis of study results, an estimated oral dosage of either 8.5 mg/kg twice a day or 20 mg/kg once a day of the commercial itraconazole capsules given in fish would produce adequate steady-state therapeutic blood levels in Humboldt penguins.