RESUMO
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 is an antifungal agent used in the treatment of a number of mycoses. Prior formulations (versions) of itraconazole required strict dietary requirements and often had poor absorption. A new itraconazole formulation has since been developed super bioavailable itraconazole (SUBA-itraconazole). This has no food requirements, has superior absorption and maintains effectiveness against a number of fungal infections.
Assuntos
Antifúngicos , Itraconazol , Humanos , Itraconazol/uso terapêutico , Itraconazol/farmacocinética , Itraconazol/administração & dosagem , Antifúngicos/uso terapêutico , Antifúngicos/farmacocinética , Antifúngicos/efeitos adversos , Antifúngicos/administração & dosagem , Micoses/tratamento farmacológico , Micoses/microbiologia , Histoplasmose/tratamento farmacológico , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Blastomicose/tratamento farmacológico , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/microbiologia , Disponibilidade BiológicaRESUMO
Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite.
RESUMO
Using polymers as additives to formulate ternary amorphous solid dispersions (ASDs) has successfully been established to increase the bioavailability of poorly soluble drugs, when one polymer is not able to provide both, stabilizing the drug in the matrix and the supersaturated solution. Therefore, we investigated the influence of low-viscosity hydroxypropyl cellulose (HPC) polymers as an additive in HPMC based ternary ASD formulations made by hot-melt extrusion (HME) on the bioavailability of itraconazole (ITZ). The partitioning potential of the different HPC grades was screened in biphasic supersaturation assays. Solid-state analytics were performed using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD). The addition of HPCs, especially HPC-UL, resulted in a superior partitioned amount of ITZ in biphasic supersaturation assays. Moreover, the approach in using HPCs as an additive in HPMC based ASDs led to an increase in partitioned ITZ compared to Sporanox® in biorelevant biphasic dissolution studies. The results from the biphasic dissolution experiments correlated well with the in vivo studies, which revealed the highest oral bioavailability for the ternary ASD comprising HPC-UL and HPMC.
RESUMO
We analyzed the relationship between itraconazole (ITZ) and hydroxy-itraconazole (OH-ITZ) levels in 1,223 human samples. Overall, there was a statistically significant correlation between ITZ and OH-ITZ levels (Pearson's r, 0.7838), and OH-ITZ levels were generally higher than ITZ levels (median OH-ITZ:ITZ ratio, 1.73; range, 0.13 to 8.96). However, marked variability was observed throughout the range of ITZ concentrations. Thus, it is difficult to predict OH-ITZ concentrations based solely on ITZ levels.
Assuntos
Antifúngicos , Itraconazol , Antifúngicos/uso terapêutico , HumanosRESUMO
We describe the development and validation of a novel liquid chromatography assay (HPLC/PDA) for simultaneous quantification of voriconazole, itraconazole, and posaconazole, as well as some of their major metabolites, voriconazole N-oxide and hydroxy-itraconazole, in human serum. Analytes were detected using a PDA system that allows the characterization of the specific UV spectra of each compound. The assay exhibited linearity between 0.25-16â¯mg/L for all the compounds tested. The accuracy and within- and between-day precision of the assay were in acceptable ranges. We successfully quantified the azoles and some of their metabolites in a collection of clinical samples collected from treated patients. The method also allows assessing the metabolic rate of several azoles being useful to predict the metabolic profile of a particular patient and to anticipate toxicity or efficacy during the treatment.
Assuntos
Antifúngicos/sangue , Azóis/sangue , Cromatografia Líquida de Alta Pressão/métodos , Soro/química , Humanos , Itraconazol/sangue , Triazóis/sangue , Voriconazol/sangueRESUMO
Nowadays in animal studies, it is important to comply with the so-called Three Rs rule by replacing or reducing the number of tested animals. Volumetric absorptive microsampling (VAMS) can be used to collect small quantities (10 or 20µL) of whole blood, thereby limiting the amount of animals needed. In this study, a quantitative method was developed and subsequently validated for the poorly soluble drug itraconazole (ITZ) using VAMS and ultra-high performance liquid chromatography (UHPLC) coupled to tandem mass spectrometry (MS). A proof of concept study showed that the optimized method is applicable to test the bioavailability of drug formulations containing ITZ. Using VAMS, smaller blood volumes can be taken per sampling point (10-20µL instead of the conventional 0.2-0.5mL) avoiding the sacrifice of animals. Moreover, the same rats can be used to compare different drug formulations which strengthens the validity of the results. In long-term bioavailability studies, it is necessary to guarantee the stability of the tested drugs supported on VAMS devices. In this study, we show that ITZ was only stable for 24h after collection with VAMS, but for at least two weeks by the storage of extracted samples at -80°C.
Assuntos
Itraconazol/sangue , Espectrometria de Massas em Tandem , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos , Meia-Vida , Itraconazol/isolamento & purificação , Itraconazol/farmacocinética , Masculino , Ratos , Ratos Wistar , Solventes/químicaRESUMO
A high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) assay was developed and validated for simultaneous determination of itraconazole (ITZ), hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ) and N-desalkyl itraconazole (ND-ITZ) concentration in human plasma. One hundred and fifty microliters of human plasma were extracted using a solid-supported liquid extraction (SLE) method and the final extracts were analyzed using reverse-phase chromatography and positive electrospray ionization mass spectrometry. The standard curve range is 5-2500 ng/mL for ITZ and OH-ITZ and 0.4-200 ng/mL for keto-ITZ and ND-ITZ. The curve was fitted to a 1/x(2) weighted linear regression model for all analytes. The precision and accuracy of the LC-MS/MS assay based on the five analytical quality control (QC) levels were well within the acceptance criteria from both FDA and EMA guidance for bioanalytical method validation. Average extraction recovery was 97.4% for ITZ, 112.9% for OH-ITZ, 103.4% for keto-ITZ, and 102.3% for ND-ITZ across their respective curve range. Matrix factor was close to 1.0 at both high and low QC levels of all 4 analytes, which indicates minimal ion suppression or enhancement in our validated assay. Itraconazole and all three metabolites are stable in human plasma for 145 days stored at -70 °C freezers. The validated assay was successfully applied to a clinical study, which has a drug-drug interaction (DDI) arm using ITZ as a cytochrome P450, family 3, subfamily A (CYP3A) inhibitor.
Assuntos
Cromatografia Líquida/métodos , Itraconazol/sangue , Espectrometria de Massas em Tandem/métodos , Cromatografia de Fase Reversa , Interações Medicamentosas , Estabilidade de Medicamentos , Humanos , Modelos LinearesRESUMO
A highly sensitive, selective, and precise ultra-performance liquid chromatography tandem mass spectrometry method was developed and validated for simultaneous quantification of itraconazole and hydroxy itraconazole in human plasma by a single liquid-liquid extraction step. The precursor to product ion transitions of m/z 705.3/392.3, m/z 721.2/408.3 and m/z 708.2/435.4 were used to detect and quantify itraconazole, hydroxy itraconazole and itraconazole-d3 respectively. The lower limit of quantitation was found to be 0.500 ng/mL for itraconazole and 1.00 ng/mL for hydroxy itraconazole. The mean recoveries for itraconazole and hydroxy itraconazole were found to be 100.045% and 100.021%, respectively. This developed method with a chromatographic run time of 2.0 min was successfully applied to a bioequivalence study of 100 mg itraconazole capsule.
RESUMO
A highly sensitive, selective, and precise ultra-performance liquid chromatography tandem mass spectrometry method was developed and validated for simultaneous quantification of itraconazole and hydroxy itraconazole in human plasma by a single liquid-liquid extraction step. The precursor to product ion transitions of m/z 705.3/392.3, m/z 721.2/408.3 and m/z 708.2/435.4 were used to detect and quantify itraconazole, hydroxy itraconazole and itraconazole-d3 respectively. The lower limit of quantitation was found to be 0.500 ng/mL for itraconazole and 1.00 ng/mL for hydroxy itraconazole. The mean recoveries for itraconazole and hydroxy itraconazole were found to be 100.045% and 100.021%, respectively. This developed method with a chromatographic run time of 2.0 min was successfully applied to a bioequivalence study of 100 mg itraconazole capsule.
RESUMO
OBJECTIVE: To establish a high-performance liquid chromatographic(HPLC)-fluorometric method for the concentration determination of itraconazole (ITZ) and its metabolite hydroxy-itraconazole(HITZ) in rabbit plasma simultaneously.METHODS: Separation was achieved with Agilent Eclipse C18,the mobile phase consisted of acetonitrile(adjusted to pH=2.5 with 85% phosphoric acid)-water(63∶37),and the flow rate was 1.0 mL?min-1.The excitation and emission wavelengths were 260 nm and 365 nm.The analysis was performed at room temperature..RESULTS: The linear concentration range of ITZ and HITZ were 7.4～296 0 ng?mL-1(r=0.999 1)and 5.4～216 0 ng?mL-1(r=0.999 3), respectively.The limit of detection was 0.518 and 0.318 ng?mL-1,respectively.The extraction and method recovery rate of ITZ and HITZ were more than 80%.The intra-day and inter-day RSD of ITZ and HITZ were less than 4.47%. CONCLUSIONS: The method is simple,sensitive,accurate and reliable for monitoring ITZ and HITZ in rabbit plasma and pharmacokinetic studies.