Bioavailability Of Posaconazole Research Articles

Development of biocompatible lipid-polymer hybrid nanoparticles for enhanced oral absorption of posaconazole: A mechanistic in vitro and in silico assessment

The current research focuses on the development of lipid-polymer hybrid nanoparticles (LPHNs) designed to enhance the solubility and bioavailability of posaconazole (PCZ). PCZ, an antifungal drug, faces challenges due to its poor water solubility, resulting in inconsistent absorption and limited bioavailability. LPHNs composed of stearic acid and poly-δ-decalactone (PDL) were successfully fabricated and characterized. The optimized formulation (P-LPHN4) exhibited a particle size of 104.0 nm, negative zeta potential (−38.9 mV), high drug loading (19.5 %), and efficient encapsulation (82.6 %). In vitro release studies demonstrated sustained drug release over 18 h, with P-LPHN4 displaying the highest drug release (92 %). Stability studies revealed good physical stability over 45 days with no significant changes in particle size, zeta potential, and PDI. In silico simulations using GastroPlus® predicted significantly improved intestinal absorption and systemic exposure for P-LPHN4 compared to the pure drug suspension in a simulated rat model. The model predicted a higher peak plasma concentration (Cmax) for P-LPHN4 (∼0.012 μg/mL) compared to the PCZ suspension (∼0.0058 μg/mL). The model identified the duodenum and jejunum as primary absorption sites for both formulations, with P-LPHNs showing significantly higher overall absorption (84.5 %) compared to the suspension (47.5 %). Simulation results revealed a dose-dependent increase in both Cmax and AUC with increasing oral P-LPHN4 dose, while Tmax remained unaffected. In conclusion, the developed posaconazole-loaded lipid-polymer hybrid nanoparticles (P-LPHN4) showed promising results in terms of enhanced drug release, stability, and bioavailability.

Preparation, optimization, and In vitro drug release study of microemulsions of posaconazole

Self-emulsifying drug delivery systems (SEDDS) are novel carriers that could be used to improve the oral bioavailability of drugs with low water solubility. This study aims to develop stable microemulsions (MEs) as SEDDS that enhance the oral bioavailability of posaconazole (PSC) (BCS Class II compound). The other objective of this study was to optimize the impact of various factors affecting the formation, physicochemical characteristics, and stability of PSC-loaded SEDDS.The MEs were formed by mixing oil, surfactants, and cosurfactants based on the water titration approach. Different formulations were made and studied to characterize each formulation. In the optimization of the ME composition, the solubility study of PSC and the triangular phase diagram with various components (i.e., oils, surfactants, and co-surfactants) were taken into consideration. After selecting the best formulations, their physicochemical properties, including average particle size, polydispersity index, zeta potential, formulation stability, and turbidity, were investigated. Finally, the formulations were used for invitro drug release study. The results of this work prove that the selection of proper combinations of components allows for reaching drug-controlled delivery formulation. Additionally, the drug's effectiveness is enhanced with the optimization and development of SEDDS so that it reduces the total dose, thereby minimizing its side effects.

Posaconazole bioavailability of the solid oral tablet is reduced during severe intestinal mucositis

ObjectivesThis study aimed to describe the absolute oral bioavailability of the solid oral formulation of posaconazole and the impact of severe intestinal mucositis in haematology patients. This study also aimed to describe posaconazole protein binding in haematology patients. MethodsA pharmacokinetic study was performed of patients receiving induction chemotherapy or a haematopoietic cell transplantation who were randomized to receive 7 days of intravenous posaconazole therapy followed by 9 days of oral therapy, or vice versa. Patients received a posaconazole licensed dose until day 12, after which a reduced once-daily dose of 200 mg was given. At days 7, 12, and 16, blood samples were obtained for pharmacokinetic curves, and trough samples were collected on all other days. Total and unbound posaconazole pharmacokinetics were analyzed by population pharmacokinetic modelling. The presence of severe intestinal mucositis was assessed by plasma citrulline levels and analyzed as a binary covariate using 10 μmol/L as the cut-off. Monte Carlo simulations were performed to simulate posaconazole exposure at a steady state. ResultsTwenty-three patients were included for analysis, with 581 total posaconazole concentrations and 91 paired unbound concentrations. Absolute bioavailability in the final model was estimated at 51.4% (percentage relative standard error (%RSE): 56.5) and 67.6% (%RSE: 75.0) in patients with and without severe intestinal mucositis, respectively. Posaconazole unbound fraction was estimated at 2.7% (%RSE: 3.9). DiscussionPosaconazole bioavailability is reduced in haematological patients with severe intestinal mucositis, requiring an increase in oral posaconazole dose to 400 mg twice daily on day 1, followed by 400 mg once daily or a switch to intravenous therapy.

PBPK modeling of CYP3A and P-gp substrates to predict drug-drug interactions in patients undergoing Roux-en-Y gastric bypass surgery.

Roux-en-Y gastric bypass surgery (RYGBS) is an effective surgical intervention to reduce mortality in morbidly obese patients. Following RYGBS, the disposition of drugs may be affected by anatomical alterations and changes in intestinal and hepatic drug metabolizing enzyme activity. The aim of this study was to better understand the drug-drug interaction (DDI) potential of CYP3A and P-gp inhibitors. The impacts of RYGBS on the absorption and metabolism of midazolam, acetaminophen, digoxin, and their major metabolites were simulated using physiologically-based pharmacokinetic (PBPK) modeling. PBPK models for verapamil and posaconazole were built to evaluate CYP3A- and P-gp-mediated DDIs pre- and post-RYGBS. The simulations suggest that for highly soluble drugs, such as verapamil, the predicted bioavailability was comparable pre- and post-RYGBS. For verapamil inhibition, RYGBS did not affect the fold-change of the predicted inhibited-to-control plasma AUC ratio or predicted inhibited-to-control peak plasma concentration ratio for either midazolam or digoxin. In contrast, the predicted bioavailability of posaconazole, a poorly soluble drug, decreased from 12% pre-RYGBS to 5% post-RYGBS. Compared to control, the predicted posaconazole-inhibited midazolam plasma AUC increased by 2.0-fold pre-RYGBS, but only increased by 1.6-fold post-RYGBS. A similar trend was predicted for pre- and post-RYGBS inhibited-to-control midazolam peak plasma concentration ratios (2.0- and 1.6-fold, respectively) following posaconazole inhibition. Absorption of highly soluble drugs was more rapid post-RYGBS, resulting in higher predicted midazolam peak plasma concentrations, which was further increased following inhibition by verapamil or posaconazole. To reduce the risk of a drug-drug interaction in patients post-RYGBS, the dose or frequency of object drugs may need to be decreased when administered with highly soluble inhibitor drugs, especially if toxicities are associated with plasma peak concentrations.

The tablet formulation of posaconazole: clinical pharmacology and the use in patients with hematologic malignancies

Posaconazole is a broad-spectrum triazole antifungal agent with potent activity against various fungi, including yeast and molds, including Mucorales, what makes a key difference with itraconazole and voriconazole. Clinical studies have demonstrated his efficacy for prophylaxis against invasive fungal infections in hematological patients at high risk (with acute myeloid leukemia, myelodysplastic syndrome, aplastic anemia, and in patients after hematopoietic stem cell transplantation, especially with graft versus host disease). Posaconazole also use as salvage therapy against invasive aspergillosis, mucormycosis and some other systemic mycoses. For today there are 3 posaconazole formulations – oral suspension, modify release tablet and intravenous solution (not registered in Russia at the time of writing this paper). As far as bioavailability of posaconazole following administration by oral suspension is highly variable with low unstable plasma concentrations and there are number of factors with negatively influence to the pharmacokinetic profile of suspension a delayed-release tablet was developed using hot-melt extrusion technology with a pH-sensitive polymer. The tablet formulation releases the drug in the intestine, and this leads to the enhanced bioavailability and increased posaconazole exposure parameters and, as a result, to a higher efficacy. This was demonstrated in pre-clinical, early phase clinical studies and confirmed with data from real practice. The tablet formulation has well tolerability profile with a low incidence of clinically significant adverse events. For today posaconazole included in all relevant clinical recommendations with high levels of evidence, including prophylaxis of invasive mycoses and therapy of their refractory forms, while the authors agree that for the oral therapy a preference should be given to the tablet formulation of posaconazole.

In vitro and in vivo evaluation of a posaconazole-sulfobutyl ether-β-cyclodextrin inclusion complex.

Posaconazole (PCZ) is a triazole antifungal agent with an extended spectrum of antifungal activity. It is approved for the prophylaxis of invasive fungal infections in patients with neutropenia or in hematopoietic stem cell transplant recipients undergoing high-dose immunosuppressive therapy for graft-vs-host disease, and for the treatment of fungal infections. However, its pharmacological effects are severely limited owing to its poor solubility and low bioavailability. In order to solve these problems, a sulfobutyl ether-β-cyclodextrin compound was used to prepare an intramuscular injection to improve the bioavailability of posaconazole. The extracorporeal dissolution rate of posaconazole was markedly improved by this inclusion complex with >90% being released within 5 min, and the in vivo pharmacokinetics were studied using a HPLC/MS/MS method for quantifying posaconazole and the posaconazole-sulfobutyl ether-β-cyclodextrin inclusion complex in rat blood. Posaconazole and an internal standard, itraconazole, were extracted by protein precipitation using acetonitrile. The concentration range of posaconazole was 0.05-4.0 μg/mL with good linearity (r = 0.9980), the peak concentrations of pure posaconazole and the inclusion complex were 0.565 ± 0.102 μg/mL and 1.12 ± 0.091 μg/mL, the values for AUC0-t were 12.2 ± 2.5 and 19.9 ± 2.5 μg h/mL, and the values for AUC0-∞ were 16.4 ± 3.2 and 25.0 ± 3.5 μg h/mL, respectively. The main pharmacokinetics parameters showed significant differences (P<0.01). Compared with pure posaconazole, the posaconazole-sulfobutyl ether-β-cyclodextrin inclusion complex markedly improved the bioavailability of posaconazole.

Preparation and evaluation of posaconazole-loaded enteric microparticles in rats

Objectives: Posaconazole (POS) is an antifungal compound which has a low oral bioavailability. The aim of this study was to prepare POS enteric microparticles to enhance its oral bioavailability.Methods: POS enteric microparticles were prepared with hypromellose acetate succinate (HPMCAS) via the spray drying method. The solvent mixtures of acetone and ethanol used in the preparation of the microparticles were optimized to produce the ideal POS enteric microparticles. Multivariate data analysis using a principal component analysis (PCA) was used to find the relationship among the HPMCAS molecular characteristics, particle properties and drug release kinetics from the spray dried microparticles.Key findings: The optimal spray solvent mixtures were critical to produce the POS microparticles with the defined polymer entanglement index, drug surface enrichment, particle size and drug loading. The HPMCAS molecular characteristics affected the microscopic connectivity and diffusivity of polymer matrix and eventually influenced the drug release behavior, and enhanced the bioavailability of POS.Conclusions: These studies suggested that the selection of suitable solvent mixtures of acetone and ethanol used in the spray drying of the microparticles was quite important to produce the entangled polymer structures with preferred polymer molecular properties of polymer coiling, overlap concentration and entanglement index. Additional studies on particle size and surface drug enrichment eventually produced HPMCAS-based enteric microparticles to enhance the oral bioavailability of POS.

Pharmacokinetics and safety of posaconazole delayed-release tablets for invasive fungal infections

Posaconazole is a broad-spectrum triazole antifungal agent with potent activity against various pathogenic fungi, including yeast and moulds. Clinical studies have demonstrated that this agent is efficacious as prophylaxis against invasive fungal infections in patients at high risk, and may also be useful as salvage therapy against invasive aspergillosis and mucormycosis. However, the bioavailability of posaconazole following administration by oral suspension, which was the only formulation clinically available for many years, is highly variable and negatively influenced by several factors. Because of this, many patients had subtherapeutic or undetectable posaconazole levels when the oral suspension was used. To overcome this limitation, a delayed-release tablet was developed and is now available for clinical use. Hot-melt extrusion technology is used to combine a pH-sensitive polymer with posaconazole to produce a formulation that releases the drug in the elevated pH of the intestine where absorption occurs rather than in the low-pH environment of the stomach. This results in enhanced bioavailability and increased posaconazole exposure. Studies in healthy volunteers have demonstrated significantly higher and more consistent exposures with the tablet formulation compared to the oral suspension. In addition, pharmacokinetic parameters following administration of the tablets were not significantly affected by medications that raise gastric pH or increase gastric motility, and the tablets could also be administered without regard to food. Similar results have also been found in patients at high risk for invasive fungal infections who have received posaconazole tablets. The tablet formulation also appears to be well tolerated to date, although data regarding clinical efficacy are needed.

CP-156 Effect of medical staff training on posaconazole exposure in neutropenic patients

BackgroundPosaconazole (PCZ), an orally-administered extended spectrum antifungal agent, is used in the prophylaxis and salvage treatment of invasive fungal infections (IFIs) in patients receiving chemotherapy or haematopoietic stem cell transplantation....

Therapeutic Drug Monitoring of Posaconazole in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome

Posaconazole is a broad-spectrum triazole antifungal available as an oral suspension. Pharmacokinetic data showed a high variability of plasma posaconazole concentrations (PPCs) in patients, suggesting a potential interest in drug monitoring. The aim of our prospective study was to measure the PPCs in prophylactically treated patients to evaluate the impact of different factors on these concentrations. In 40 patients treated prophylactically with posaconazole for acute myeloid leukemia or myelodysplastic syndrome between February 2009 and August 2010, PPCs were measured at day 7 of treatment and then twice weekly. Demographic data, clinical data (including gastrointestinal disorders, comedications, and treatment compliance), caloric and fat intake, and biological data were collected and evaluated. We obtained 275 measurements of PPCs, with a median of 430 ng/ml. PPCs were significantly lower in patients with mucositis (P < 0.001), nausea (P = 0.03), diarrhea (P = 0.03), or vomiting (P = 0.05). PPCs were higher in patients with a higher caloric intake (P = 0.02), while the proportion of fat intake had no influence on PPCs (P = 0.84). The concomitant use of proton pump inhibitors decreased the PPCs (P = 0.02), while the use of tacrolimus increased the PPC (P = 0.03). In the multivariate analysis, the factors influencing the PPCs independently were the concomitant use of tacrolimus (P < 0.001), the presence of mucositis (P = 0.01), and food intake (P = 0.02). Our study confirmed the high variability of posaconazole bioavailability and showed the significant influence of gastrointestinal disorders, food intake, and concomitant medication on the PPCs. However, the optimal PPCs still remain to be defined and correlated with clinical efficacy.

Pharmacokinetics of Different Dosing Strategies of Oral Posaconazole in Patients with Compromised Gastrointestinal Function and Who Are at High Risk for Invasive Fungal Infection

The aim of this study was to assess different dosing strategies that may result in increased posaconazole bioavailability in patients with compromised gastrointestinal function and at high risk for invasive fungal infections. Patients undergoing chemotherapy and at risk for compromised gastrointestinal function received open-label posaconazole at 200 mg three times daily (TID) on days 1 to 8. Patients were randomized to one of three open-label dosing regimens of posaconazole on days 9 to 15: 200 mg TID, 400 mg twice daily (BID), or 400 mg TID. The plasma concentrations of interest on days 8 and 15 were 500 and 700 ng/ml, respectively; day 2 plasma concentrations of 250 and 350 ng/ml were chosen as levels that might result in steady-state concentrations of >500 and >700 ng/ml, respectively. A total of 75 patients enrolled; 52/75 (69%) completed the study, and 49/75 were included in the pharmacokinetic analyses. Mean plasma concentrations were 230, 346, and 637 ng/ml on days 2, 3, and 8, respectively. The day 15 values were 660, 930, and 671 ng/ml for 200 mg TID, 400 mg BID, and 400 mg TID, respectively. In 12 patients with a day 8 posaconazole concentration of <250 ng/ml, an overall benefit of the higher two doses was not apparent, suggesting that a subset of patients has low steady-state plasma concentrations. A change in dosing regimen on day 9 did not lead to higher exposures in these "poor absorbers" on day 15. Poor absorption may be enhanced with a high-fat meal, a nutritional supplement, or acidification.

Effect of pH and Comedication on Gastrointestinal Absorption of Posaconazole

Posaconazole (Noxafil®) is an extended-spectrum triazole antifungal agent for prevention and treatment of invasive fungal infections. An inadequate dietary intake and abnormal gastric pH levels are common in critically ill patients receiving antifungal treatment with posaconazole, resulting in unpredictable bioavailability and sub-therapeutic plasma concentrations. This study was carried out to elucidate the impact of pH on posaconazole absorption and to explore the underlying mechanisms of enhanced intestinal absorption when coadministering an acidic carbonated beverage. In contrast to previously published studies, in which only plasma concentrations were determined, we also explored the gastric and intestinal behaviour of posaconazole after a single oral dose. A crossover study was performed in five healthy subjects. A single dose (10 mL) of posaconazole suspension (40 mg/mL) was administered orally in four different conditions: with 330 mL of water (condition 1); with 330 mL of a cola beverage [Coca-Cola®] (condition 2); with 330 mL of water following intake of the proton pump inhibitor esomeprazole 40 mg once daily for 3 days (condition 3); or with 330 mL of Coca-Cola® following intake of esomeprazole 40 mg once daily for 3 days (condition 4). After administration, gastrointestinal fluid and plasma samples were collected at regular time points, and posaconazole concentrations were determined. Compared with administration with water, coadministration of Coca-Cola® did not alter the pH of the intraluminal environment but did significantly increase posaconazole gastric concentrations (+102%; p < 0.001) and systemic exposure (+70%; p < 0.05). This enhancement could be attributed to improved posaconazole solubility in Coca-Cola® and prolonged gastric residence. Coadministration of esomeprazole led to an increased gastric pH, which was accompanied by decreased posaconazole absorption; the mean plasma and gastric area under the concentration-time curve (AUC) values decreased by 37% and 84%, respectively. Simultaneous intake of Coca-Cola® could not completely compensate for the increase in pH induced by esomeprazole; compared with the reference condition, the mean plasma and gastric AUC values were still decreased by 19% and 73%, respectively. A good correlation between plasma and gastric posaconazole concentrations was observed (r = 0.8165; p < 0.0001), indicating that dissolution in the stomach dictates absorption of posaconazole. These results demonstrate that coadministration of Coca-Cola® has a positive effect on posaconazole bioavailability in the fasted state. However, it can only be considered a partially efficient strategy to increase absorption in patients with inadequate food intake who exhibit abnormal gastric pH levels due to coadministration of acid-suppressive agents.

Clinical pharmacodynamics and pharmacokinetics of the antifungal extended‐spectrum triazole posaconazole: an overview

In recent years, the antifungal triazole posaconazole has become increasingly important for the prophylaxis and treatment of systemic mycoses. Although oral bioavailability of posaconazole can be enhanced by concomitant food intake and administration in divided daily doses, increased gastric pH or gut motility, as well as enzyme-inducing drugs, can result in lower plasma concentrations than expected. Whether therapeutic drug monitoring can reduce the risk of treatment failures by avoiding sub-therapeutic plasma concentrations needs further examination. Based on the ability of posaconazole to inhibit cytochrome P450 3A4, several drug interactions can be expected, especially with agents that undergo extensive first-pass effect through the gut and the liver. However, more information is needed regarding dose modifications during concomitant administration of posaconazole with drugs in certain categories, such as vinca alkaloids and retinoids, along with selected individual drugs such as everolimus.

Therapeutic Drug Monitoring of Posaconazole in Hematology Patients: Experience with a New High-Performance Liquid Chromatography-Based Method

Parallel administration of the proton pump inhibitor (PPI) esomeprazole has been shown to decrease oral bioavailability of posaconazole in healthy volunteers. We prospectively analyzed serum samples (n = 59) obtained from hematology patients (n = 27) under posaconazole prophylaxis. Patients treated concomitantly with pantoprazole had significantly lower posaconazole levels than patients without PPI treatment (median levels of 630 microg/liter versus 1,125 microg/liter, respectively). These results suggest that drug monitoring is relevant when posaconazole and pantoprazole are administered concomitantly.

Pharmacokinetic/Pharmacodynamic Profile of Posaconazole

Posaconazole is a recently approved lipophilic triazole antifungal agent that exhibits potent and broad-spectrum antifungal activity in vitro and in vivo against most Candida spp., Cryptococcus neoformans, Aspergillus spp., many Zygomycetes, endemic fungi and dermatophytes. It has been documented that posaconazole has potency and spectrum of activity similar to those of itraconazole and superior to those of fluconazole against clinically important isolates of Candida spp., C. neoformans and Aspergillus spp. This new triazole has been developed for the treatment of fungal infections, which most often occur in severely immunocompromised patients, such as organ transplant patients or cancer patients undergoing chemotherapy. Since posanconazole has low solubility in aqueous and acidic media, its absorption is dose limited and significantly dependent upon food intake. The time to reach the maximum plasma concentration has been reported to be 5-8 hours following oral administration of a single dose. The relative bioavailability of posaconazole has been estimated to be significantly different among regimens and has been observed to be significantly increased by administration in divided doses. Posaconazole binds predominantly to albumin, and the extent of protein binding is high (>98%). Posaconazole has a large mean apparent volume of distribution after oral administration (V(d)/F), which is approximately 5-25 L/kg, suggesting extensive extravascular distribution and penetration into intracellular spaces. The V(d)/F is influenced by the dosage regimen. Since food significantly increases its bioavailability, posaconazole should be administered with a full meal whenever possible, to ensure optimal absorption. Posaconazole primarily circulates in plasma and then is widely distributed to the tissues and is slowly eliminated. Posaconazole is not metabolized to a significant extent through the cytochrome P450 (CYP) enzyme system and also has no effect on the CYP isoenzymes of 1A2, 2C8, 2C9, 2D6 and 2E1. The limited metabolism of posaconazole is mediated predominantly through phase 2 biotransformations via uridine diphosphate glucuronosyltransferase enzyme pathways. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Since posaconazole is an inhibitor primarily of CYP3A4, plasma concentrations of drugs that are predominantly metabolized by CYP3A4 may be increased by posaconazole. Posaconazole has a median terminal elimination half-life of 15-35 hours. The renal elimination of posaconazole is less than 1 mL/h, which is negligible compared with the mean total oral clearance of 16.3 L/h. Posaconazole shows potent in vitro activity against yeasts such as Candida spp. and C. neoformans, and against a range of moulds such as Aspergillus spp., as well as many dimorphic fungi and dermatophytes. Posaconazole has been shown to improve survival and/or to reduce the fungal tissue burden in animals infected with Blastomyces dermatitidis, C. neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Coccidioides immitis or Pseudallescheria boydii. The predictive pharmacokinetic/pharmacodynamic parameter for posaconazole treatment efficacy--the ratio between the mean free-drug area under the plasma concentration-time curve from 0 to 24 hours and the minimum inhibitory concentration (AUC(24)/MIC)--is about 17, which is similar to the value observed for other azoles in this infection model of disseminated Candida albicans infection.

Effect of Varying Amounts of a Liquid Nutritional Supplement on the Pharmacokinetics of Posaconazole in Healthy Volunteers

The aim of this single-center, phase 1, randomized, 5 by 5 crossover, open-label study was to determine the effects of varying amounts of a nutritional supplement (Boost Plus) on the pharmacokinetics of posaconazole in 30 healthy volunteers. After an overnight fast, subjects were administered a single dose of 400 mg posaconazole oral suspension alone or following Boost Plus (8 fluid ounces [oz] [240 ml], 4 oz [120 ml], 2 oz [60 ml], or 1 oz [30 ml]). Subjects were randomized to receive all five treatments in different sequences, with a 14-day washout between treatments. Primary pharmacokinetic variables--area under the concentration-time curve from time zero to the time of the final quantifiable sample (AUC(tf)), maximum observed plasma concentration (C(max)), time to C(max) (T(max)), and relative bioavailability--were assessed up to 5 days postdose. Safety assessments included testing for adverse events, clinical laboratory tests, measurement of vital signs, physical examinations, and electrocardiograms. Posaconazole bioavailability increased almost linearly with increasing amounts of Boost Plus. Based on log-transformed data, the relative bioavailabilities (AUCs) of posaconazole were 35% (fasting), 48% (1 oz), 60% (2 oz), and 77% (4 oz) of the level reached in the presence of 8 oz Boost Plus, whereas T(max) was unaffected. Compared with the levels reached under fasting conditions, posaconazole C(max) and AUC values increased 3.5- and 2.9-fold, respectively, when given with 8 oz Boost Plus. Single doses of posaconazole at 400 mg alone and with 1, 2, 4, or 8 oz Boost Plus were safe and well tolerated in healthy subjects.

Posaconazole: A Next-Generation Triazole Antifungal

Posaconazole is a new drug in the triazole class that has recently been investigated in pivotal Phase III clinical trials. Its antifungal activity is based on the inhibition of the fungal ergosterol synthesis. As demonstrated in vitro, posaconazole exhibits fungicidal activity against Aspergillus spp., Candida spp. and zygomycetes. Currently, posaconazole is only available as an oral suspension. Food consumption affects the bioavailability of posaconazole, while the exposure to posaconazole increases in a dose-proportional manner with a saturation of absorption occurring with a daily dose over 800 mg. Posaconazole is well tolerated without an increase in risk of any treatment-related adverse events during prolonged treatment for 6 or more months (n = 108). Posaconazole has been recently approved by the US FDA and other regulatory bodies for the treatment of oropharyngeal candidiasis, and the prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients. As demonstrated in two pivotal Phase III trials, posaconazole prophylaxis of invasive fungal infection in patients severely immunocompromised by graft-versus-host disease (n = 600) or neutropenia (n = 602) is superior to fluconazole and/or itraconazole prophylaxis. Significantly more patients who received posaconazole, instead of fluconazole, as treatment for oropharyngeal candidiasis sustained clinical success after the treatment was stopped. Preliminary data from a subgroup analysis (n = 24) of two salvage therapy trials for invasive fungal infections, as well as single case reports and series and in vitro studies, suggest that posaconazole might be an attractive oral treatment alternative for zygomycosis.

Oral Bioavailability of Posaconazole in Fasted Healthy Subjects

Posaconazole is a potent, extended-spectrum triazole antifungal agent currently in clinical development for the treatment of invasive fungal infections. This study was conducted to compare the bioavailability and resulting serum concentrations of posaconazole 800 mg following administration of three different dose regimens to fasting adults. This was a randomised, open-label, three-way crossover study. Subjects fasted 12 hours before and 48 hours after the administration of posaconazole oral suspension (800 mg) given as a single dose (regimen A), 400 mg every 12 hours (regimen B) or 200 mg every 6 hours (regimen C). Plasma posaconazole concentrations were determined for 48 hours after the initial dose and subjects completed a 1-week washout period between treatment regimens. A one-compartment oral model with first-order rate of absorption and first-order rate of elimination was fitted to the plasma concentration-time data. Differences in exposure were investigated by allowing the bioavailability fraction to vary among regimens. A total of 18 healthy men were enrolled in and completed the study. Posaconazole relative bioavailability was estimated to be significantly different among regimens (p < 0.0001) and increased with the number of doses, such that regimen B/regimen A = 1.98 +/- 0.35, representing a 98% increase, and regimen C/regimen A = 3.20 +/- 0.69, or a 220% increase. With use of the one-compartment model, the population steady-state values for area under the concentration-time curve over 24 hours were predicted to be 3900, 7700 and 12 400 microg.h/L, with average plasma concentrations of 162, 320 and 517 microg/L for regimens A, B and C, respectively. These data suggest that divided daily dose administration (every 12 or 6 hours) significantly increases posaconazole exposure under fasted conditions.