Itraconazole is an orally active antifungal agent that has complex and highly variable absorption kinetics that is highly affected by food. This study aimed to develop a population pharmacokinetic ...model for itraconazole and the active metabolite hydroxyitraconazole, in particular, quantifying the effects of food and formulation on oral absorption. Plasma pharmacokinetic data were collected from seven phase I crossover trials comparing the SUBA-itraconazole and Sporanox formulations of itraconazole. First, a model of single-dose itraconazole data was developed, which was then extended to the multidose data. Covariate effects on itraconazole were then examined before extending the model to describe hydroxyitraconazole. The final itraconazole model was a 2-compartment model with oral absorption described by 4-transit compartments. Multidose kinetics was described by total effective daily dose- and time-dependent changes in clearance and bioavailability. Hydroxyitraconazole was best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose data and a time-dependent clearance for the multidose data. The relative bioavailability of SUBA-itraconazole compared to that of Sporanox was 173% and was 21% less variable between subjects. Food resulted in a 27% reduction in bioavailability and 58% reduction in the transit absorption rate constant compared to that with the fasted state, irrespective of the formulation. This analysis presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature performed in healthy subjects. The presented model can be used for simulating food effects on itraconazole exposure and for performing prestudy power analysis and sample size estimation, which are important aspects of clinical trial design of bioequivalence studies.
Recently published studies have proposed that amorphous drug nanoparticles in gastrointestinal fluids may be beneficial for the absorption of poorly soluble compounds. Nanosized drug particles are ...known to provide rapid dissolution rates and, in some instances, a slight increase in solubility. However, in recent studies, the differences observed in vivo could not be explained solely by these attributes. Given the high dose and very low aqueous solubility of the study compounds, rapid equilibration to the drug-saturated solubility in gastrointestinal fluid would occur independent of the presence of nanoparticles. Alternatively, it has been proposed that drug nanoparticles (ca. ≤ 200 to 300 nm) may provide a "shuttle" for drug across the unstirred water layer (UWL) adjacent to the intestinal epithelium, particularly for low solubility/lipophilic compounds where absorption may be largely UWL-limited. This transport mechanism would result in a higher unbound drug concentration at the surface of the epithelium for absorption. This study evaluates this mechanism using a simple modification of the effective permeability to account for the effect of drug nanoparticles diffusing across the UWL. The modification can be made using inputs for solubility and nanoparticle size. The permeability modification was evaluated using three published case studies for amorphous formulations of itraconazole, anacetrapib, and enzalutamide, where the formation of amorphous drug nanoparticles upon dissolution resulted in improved drug absorption. Absorption modeling was performed using GastroPlus to assess the impact of the nanomodified permeability method on the accuracy of model prediction compared to in vivo data. Simulation results were compared to those for baseline simulations using an unmodified effective permeability. The results show good agreement using the nanomodified permeability, which described the data better than the standard baseline predictions. The nanomodified permeability method can be a suitable, fit-for-purpose in silico approach for evaluating or predicting oral absorption of poorly soluble, UWL-limited drugs from formulations that produce a significant number of amorphous drug nanoparticles.
Background.
The antifungal drug itraconazole inhibits angiogenesis and Hedgehog signaling and delays tumor growth in murine prostate cancer xenograft models. We conducted a noncomparative, ...randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole in men with metastatic prostate cancer.
Patients and Methods.
We randomly assigned 46 men with chemotherapy‐naïve metastatic castration‐resistant prostate cancer (CRPC) to receive low‐dose (200 mg/day) or high‐dose (600 mg/day) itraconazole until disease progression or unacceptable toxicity. The primary endpoint was the prostate‐specific antigen (PSA) progression‐free survival (PPFS) rate at 24 weeks; a 45% success rate in either arm was prespecified as constituting clinical significance. Secondary endpoints included the progression‐free survival (PFS) rate and PSA response rate (Prostate Cancer Working Group criteria). Exploratory outcomes included circulating tumor cell (CTC) enumeration, serum androgen measurements, as well as pharmacokinetic and pharmacodynamic analyses.
Results.
The high‐dose arm enrolled to completion (n = 29), but the low‐dose arm closed early (n = 17) because of a prespecified futility rule. The PPFS rates at 24 weeks were 11.8% in the low‐dose arm and 48.0% in the high‐dose arm. The median PFS times were 11.9 weeks and 35.9 weeks, respectively. PSA response rates were 0% and 14.3%, respectively. In addition, itraconazole had favorable effects on CTC counts, and it suppressed Hedgehog signaling in skin biopsy samples. Itraconazole did not reduce serum testosterone or dehydroepiandrostenedione sulfate levels. Common toxicities included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema.
Conclusion.
High‐dose itraconazole (600 mg/day) has modest antitumor activity in men with metastatic CRPC that is not mediated by testosterone suppression.
摘要
背景. 在小鼠前列腺癌异种移植模型中，抗真菌药‐‐伊曲康唑对血管生成和Hedgehog信号转导有抑制作用，并可延缓肿瘤生长。本小组开展了一项随机非对照II期研究，以评估伊曲康唑2种口服剂量在转移性前列腺癌男性患者中的抗肿瘤有效性。
患者和方法. 纳入46例未经化疗的转移性去势难治性前列腺癌（CRPC）男性，随机接受伊曲康唑低剂量（200 mg/天）或高剂量（600 mg/天）治疗，直至疾病进展或出现无法耐受的毒性反应。主要研究终点为第24周时无前列腺特异性抗原（PSA）进展生存（PPFS）率；任意一组治疗成功率达45%认为有临床意义。次要终点包括无进展生存（PFS）率和PSA反应率（前列腺癌工作组标准）。试验性转归包括循环肿瘤细胞（CTC）计数、血清雄激素测定、药代动力学及药效动力学分析。
结果. 高剂量组完成全程入组（n =29），低剂量组因达到预定无效标准而提前终止（ n =17）。第24周时，低剂量组与高剂量组的PPFS率分别为11.8%和48.0%，中位PFS时间分别为11.9周和35.9周，PSA反应率分别为0%和14.3%。此外，伊曲康唑对CTC计数有积极影响，并可抑制皮肤活检样本中的Hedgehog信号转导。伊曲康唑并不能降低血清睾酮或硫酸脱氢表雄酮水平。常见的毒性反应包括疲乏、恶心、厌食、皮疹以及低钾、高血压和水肿综合征。
结论. 高剂量伊曲康唑（600 mg/天）对非睾酮抑制性的转移性CRPC男性患者有中效抗肿瘤活性。
A noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole was conducted in men with metastatic prostate cancer.
•Quantification of itraconazole using only 10μL of whole blood.•The method has been validated and the stability of itraconazole has been assessed.•The presented method is suited to study the ...bioavailability of drug formulations.•Volumetric absorptive microsampling diminishes the number of required study animals.
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.
Understanding the dissolution mechanisms of amorphous solid dispersions (ASDs) and being able to link enhanced drug exposure with process parameters are key when formulating poorly soluble compounds. ...Thus, in this study, ASDs composed by itraconazole (ITZ) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) were formulated with different polymer grades and drug loads (DLs) and processed by spray drying with different atomization ratios and outlet temperatures. Their
performance and the ability to form drug-rich colloids were then evaluated by a physiologically relevant dissolution method. In gastric media, drug release followed a diffusion-controlled mechanism and drug-rich colloids were not formed since the solubility of the amorphous API at pH 1.6 was not exceeded. After changing to intestinal media, the API followed a polymer dissolution-controlled release, where the polymer rapidly dissolved, promoting the immediate release of API and thus leading to liquid-liquid phase separation (LLPS) and consequent formation of drug-rich colloids. However, the release of API and polymer was not congruent, so API surface enrichment occurred, which limited the further dissolution of the polymer, leading to a drug-controlled release. ASDs formulated with M-grade showed the highest ability to maintain supersaturation and the lowest tendency for AAPS due to its good balance between acetyl and succinoyl groups, and thus strong interactions with both the hydrophobic drug and the aqueous dissolution medium. The ability to form colloids increased for low DL (15%) and high specific surface area due to the high amount of polymer released until the occurrence of API surface enrichment. Even though congruent release was not observed, all ASDs formed drug-rich colloids that were stable in the solution until the end of the dissolution study (4 h), maintaining the same size distribution (ca. 300 nm). Drug-rich colloids can,
, act as a drug reservoir replenishing the drug while it permeates. Designing ASDs that are prone to form colloids can overcome the solubility constraints of Biopharmaceutics Classification System (BCS) II and IV drugs, posing as a reliable formulation strategy.
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Development of efficient ocular drug delivery system for antifungal drugs becomes a must nowadays to face and eradicate the widely spread ophthalmic fungal infections. Itraconazole, a ...triazole antifungal, is struggling to penetrate the cornea and subsequently, its efficacy is limited. The aim of this study was to enhance itraconazole corneal penetration through utilizing the minimum surfactant amount in presence of β-cyclodextrin which acted as a dissolution and permeation enhancer. β-Cyclodextrin consolidated micellar dispersions (CCMD) were prepared after an initial screening to select the composition of surfactant(s). The preparation was done according to a modified melt dispersion technique. The prepared CCMD were characterized through the analysis of their particle size, zeta potential and solubilization efficiency. The optimum formula was chosen based on a factorial response surface analysis and it was composed of 17:1 w/w surfactant/drug, 30:1 w/w cyclodextrin/drug ratios and 0.02% polyethylene oxide. This formula was subjected to in vitro characterization including release, imaging by transmission electron microscope, mucoadhesion, stability, in addition to the determination of the minimum inhibitory concentration. Moreover, the ex vivo/in vivo permeation, safety and efficacy profiles were determined. The optimized CCMD formula was found to be significantly safe, stable, mucoadhesive and efficient to permeate the drug through rabbits’ corneas. Consequently, the optimized CCMD formulation can be a promising, safe and efficient platform for the transcorneal delivery of lipophilic drugs including most antifungals.
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High speed electrospinning (HSES), compatible with pharmaceutical industry, was used to demonstrate the viability of the preparation of drug-loaded polymer nanofibers with radically ...higher productivity than the known single-needle electrospinning (SNES) setup. Poorly water-soluble itraconazole (ITRA) was formulated with PVPVA64 matrix polymer using four different solvent-based methods such as HSES, SNES, spray drying (SD) and film casting (FC). The formulations were assessed in terms of improvement in the dissolution rate of ITRA (using a “tapped basket” dissolution configuration) and analysed by SEM, DSC and XRPD. Despite the significantly increased productivity of HSES, the obtained morphology was very similar to the SNES nanofibrous material. ITRA transformed into an amorphous form, according to the DSC and XRPD results, in most cases except the FC samples. The limited dissolution of crystalline ITRA could be highly improved: fast dissolution occurred (>90% within 10min) in the cases of both (the scaled-up and the single-needle) types of electrospun fibers, while the improvement in the dissolution rate of the spray-dried microspheres was significantly lower. Production of amorphous solid dispersions (ASDs) with the HSES system proved to be flexibly scalable and easy to integrate into a continuous pharmaceutical manufacturing line, which opens new routes for the development of industrially relevant nanopharmaceuticals.
As many new active pharmaceutical ingredients are poorly water soluble, solubility enhancers are one possibility to overcome the hurdles of drug dissolution and absorption in oral drug delivery. In ...the present work a novel solubility enhancing excipient (Soluplus®) was tested for its capability to improve intestinal drug absorption. BCS class II compounds danazol, fenofibrate and itraconazole were tested both
in vivo in beagle dogs and
in vitro in transport experiments across Caco-2 cell monolayers. Each drug was applied as pure crystalline substance, in a physical mixture with Soluplus®, and as solid solution of the drug in the excipient. In the animal studies a many fold increase in plasma AUC was observed for the solid solutions of drug in Soluplus® compared to the respective pure drug. An effect of Soluplus® in a physical mixture with the drug could be detected for fenofibrate.
In vitro transport studies confirm the strong effect of Soluplus® on the absorption behavior of the three tested drugs. Furthermore, the increase of drug flux across Caco-2 monolayer is correlating to the increase in plasma AUC and
C
max
in vivo. For these poorly soluble substances Soluplus® has a strong potential to improve oral bioavailability. The applicability of Caco-2 monolayers as tool for predicting the
in vivo transport behavior of the model drugs in combination with a solubility enhancing excipient was shown. Also the improvement of a solid dispersion compared to physical mixtures of the drugs and the excipient was correctly reflected by Caco-2 experiments. In the case of fenofibrate the possible improvement by a physical mixture was demonstrated, underscoring the value of the used tool as alternative to animal studies.
The goal of this research was to evaluate an intravenous itraconazole nanosuspension dosage form, relative to a solution formulation, in the rat. Itraconazole was formulated as a nanosuspension by a ...tandem process of microcrystallization followed by homogenization. Acute toxicity, pharmacokinetics, and distribution were studied in the rat, and compared with a solution formulation of itraconazole. Efficacy was studied in an immunocompromised rat model, challenged with a lethal dose of either itraconazole-sensitive or itraconazole-resistant
C. albicans. Itraconazole nanosuspension was tolerated at significantly higher doses compared with a solution formulation. Pharmacokinetics of the nanosuspension were altered relative to the solution formulation.
C
max was reduced and
t
1/2 was much prolonged. This occurred due to distribution of the nanosuspension to organs of the monocyte phagocytic system (MPS), followed by sustained release from this IV depot. The higher dosing of the drug, enabled in the case of the nanosuspension, led to higher kidney drug levels and reduced colony counts. Survival was also shown to be superior relative to the solution formulation. Thus, formulation of itraconazole as a nanosuspension enhances efficacy of this antifungal agent relative to a solution formulation, because of altered pharmacokinetics, leading to increased tolerability, permitting higher dosing and resultant tissue drug levels.
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