Bioavailability Of Voriconazole Research Articles

FORMULATION AND DEVELOPMENT OF VORICONAZOLE TABLETS CONTAINING SOLID DISPERSION WITH ENHANCED SOLUBILITY, DISSOLUTION AND BIOAVAILABILITY

This research work enhances the solubility, dissolution and bioavailability of Voriconazole which belongs to BCS II class. Carboxymethyl tamarind gum was synthesized by using carboxymethylation of tamarind gum. Solid dispersion of Voriconazole was developed by kneading method followed by immediate release tablets. Solid dispersion characterised for solubility and instrumental analysis. Tablets were evaluated for dissolution study. Solid dispersions were confirmed by presence of distinctive peaks at 1745.58 cm-1 (C=O) and 1402 cm-1 (-COO-), using Infrared spectroscopy. The weight loss of 3.91% and 54.42 % at 100°C and in the rage of 235°C-425°C respectively was observed. 13C nuclear magnetic resonance spectrum of carboxymethyl tamarind gum displayed three distinct peaks of C1, -OH, and CH2O- group. X-ray diffraction analysis confirmed that ccarboxymethyl tamarind gum exhibits an amorphous structure. Soild dispersion of Voriconazole were developed using the kneading method, incorporating carboxymethyl tamarind gum. Compared to traditional methods, Solid dispersion formulated with carboxymethyl tamarind gum demonstrated a significant increase in solubility enhancement, ranging from 68.12 to 74.37-fold. Notably, the SD5 formulation exhibited complete release from the solid dispersion within 120 minutes. In rat models, Voriconazole levels in the bloodstream were markedly elevated with the administration of solid dispersion. Furthermore, dissolution profiles of all formulation batches showed considerable improvement. These findings shed light on effective strategies for enhancing the dissolution and bioavailability of poorly soluble drugs, thus contributing to the advancement of drug delivery systems.

Formulation and characterization studies of inclusion complexes of voriconazole for possible ocular application

In our study, Voriconazole (VOR) was selected as an active agent to be used for the treatment of ocular fungal infections. To overcome low aqueous solubility of VOR, inclusion complexes with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), hydroxypropyl-cyclodextrin (HP-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD) hydroxypropyl-γ-cyclodextrin (HP-γ-CD), methyl-β-cyclodextrin (M-β-CD) and sulfabutylether-β-cyclodextrin (SBE-β-CD) were formulated. Characterization studies revealed that inclusion complexes were formulated successfully with the lyophilization method. Aqueous solubility of VOR was enhanced up to 86 fold with the formation of the inclusion complexes. MTT analyses results revealed the safety of the complexes on 3T3 mouse fibroblast cell lines while Microbroth Dilution Method revealed the remarkable antifungal activities of the complexes. Analyses results revealed that inclusion complexes will overcome the poor ocular bioavailability of VOR resulting inefficient treatment of severe ocular fungal infections.

Improving therapeutic efficacy of voriconazole against fungal keratitis: Thermo-sensitive in situ gels as ophthalmic drug carriers

The aim of this research was to evaluate the potential use of in situ gel formulations for voriconazole ocular delivery as fungal keratitis treatment. The in situ gelling system was applied to increase residence time and the bioavailability of voriconazole in the ocular mucosa. Temperature-triggered in situ gel formulations were prepared by cold method. Poloxamer 188, poloxamer 407 and carboxymethylcellulose were used for the preparation of thermosensitive in situ ocular gel. Voriconazole concentration in formulations was 0.1% (w/w). The prepared gels were evaluated for clarity, sol-gel transition temperature, gelling capacity, pH, viscosity, FT-IR and drug content. The gelation temperatures of all the formulations were within the range of 29–34 °C. All formulations exhibited fairly uniform drug content. Furthermore, sterility, antifungal activity, stability, in vitro drug release, ex vivo permeation, and penetration and in vivo study of these formulations were also examined. Drug release results indicated that all formulations showed sustained release properties. Irritation studies showed that no ocular damage or clinically abnormal signs were observed in the cornea, conjunctiva or iris upon administration of the formulation. In conclusion, voriconazole loaded in situ gels could be offered as a promising strategy as ocular carriers for the treatment of fungal keratitis.

Bioavailability of voriconazole in hospitalised patients

An important element in antimicrobial stewardship programmes is early switch from intravenous (i.v.) to oral antimicrobial treatment, especially for highly bioavailable drugs. The antifungal agent voriconazole is available both in i.v. and oral formulations and bioavailability is estimated to be >90% in healthy volunteers, making this drug a suitable candidate for such a transition. Recently, two studies have shown that the bioavailability of voriconazole is substantially lower in patients. However, for both studies various factors that could influence the voriconazole serum concentration, such as inflammation, concomitant intake of food with oral voriconazole, and gastrointestinal complications, were not included in the evaluation. Therefore, in this study a retrospective chart review was performed in adult patients treated with both oral and i.v. voriconazole at the same dose and within a limited (≤5 days) time interval in order to evaluate the effect of switching the route of administration on voriconazole serum concentrations. A total of 13 patients were included. The mean voriconazole trough concentration was 2.28 mg/L [95% confidence interval (CI) 1.29–3.26 mg/L] for i.v. voriconazole administration and 2.04 mg/L (95% CI 0.78–3.30 mg/L) for oral administration. No significant difference was found in the mean oral and i.v. trough concentrations of voriconazole (P = 0.390). The mean bioavailability was 83.0% (95% CI 59.0–107.0%). These findings suggest that factors other than bioavailability may cause the observed difference in voriconazole trough concentrations between oral and i.v. administration in the earlier studies and stress the need for an antimicrobial stewardship team to guide voriconazole dosing.

Drug interaction between voriconazole and tacrolimus and its association with the bioavailability of oral voriconazole in recipients of allogeneic hematopoietic stem cell transplantation

In a previous study, we noted wide inter-individual variability in drug interactions between voriconazole and tacrolimus, but that analysis did not take into account the routes of administration. In the present study, we analyzed interactions between these two drugs when both agents were administered orally after allogeneic hematopoietic stem cell transplantation (HSCT); the effect of plasma voriconazole levels on the magnitude of the drug interaction was also examined. Twenty-five allogeneic HSCT recipients were evaluated. Trough concentrations of tacrolimus were measured prior to, and periodically for 7-10 days after, initiating voriconazole (400 mg/day) to determine the concentration/dose (C/D) ratio of tacrolimus. The median C/D ratio of tacrolimus increased significantly from 172.8 (range 28.6-1110.7) to 537.5 (range 127.8-1933.3) (ng/mL)/(mg/kg) (P < 0.01) following initiation of voriconazole; the median increase was 138.8 % (range -32.0 to 685.7 %). The plasma concentration of voriconazole did not correlate with the increase of the tacrolimus C/D ratio (ρ = 0.16, P = 0.44). These results indicate that oral voriconazole has a significant drug interaction with oral tacrolimus with a wide inter-individual variability, which cannot be explained by the bioavailability of voriconazole. Other possible mechanisms should be explored in future studies.

Bioavailability and Population Pharmacokinetics of Voriconazole in Lung Transplant Recipients

This study was undertaken to characterize the pharmacokinetics and bioavailability of voriconazole in adult lung transplant patients during the early postoperative period, identify factors significantly associated with various pharmacokinetic parameters, and make recommendations for adequate dosing regimens. Thirteen lung transplant patients received two intravenous infusions (6 mg/kg, twice daily [b.i.d.]) immediately posttransplant followed by oral doses (200 mg, b.i.d.) for prophylaxis. Blood samples (9/interval) were collected during one intravenous and one oral dosing interval from each patient. Voriconazole plasma concentrations were measured by high-pressure liquid chromatography (HPLC). NONMEM was used to develop pharmacokinetic models, evaluate covariate relationships, and perform Monte Carlo simulations. There was a good correlation (R(2) = 0.98) between the area under the concentration-time curve specific for the dose evaluated (AUC(0-∞)) and trough concentrations. A two-compartment model adequately described the data. Population estimates of bioavailability, clearance, V(c), and V(p) were 45.9%, 3.45 liters/h, 54.7 liters, and 143 liters. Patients with cystic fibrosis (CF) exhibited a significantly lower bioavailability (23.7%, n = 3) than non-CF patients (63.3%, n = 10). Bioavailability increased with postoperative time and reached steady levels in about 1 week. V(p) increased with body weight. Bioavailability of voriconazole is substantially lower in lung transplant patients than non-transplant subjects but significantly increases with postoperative time. CF patients exhibit significantly lower bioavailability and exposure of voriconazole and therefore need higher doses. Intravenous administration of voriconazole during the first postoperative day followed by oral doses of 200 mg or 400 mg appeared to be the optimal dosing regimen. However, voriconazole levels should be monitored, and the dose should be individualized based on trough concentrations as a good measure of drug exposure.