The variability in CYP3A4 activity determines the metabolic kinetic characteristics of ketamine.

Ketamine is a psychotropic drug that can cause significant neurological symptoms and is closely linked to the activity of the CYP3A4 enzyme. This study aimed to examine the diversity of CYP3A4 activity affects the metabolism of ketamine, focusing on genetic variation and drug-induced inhibition. We used a baculovirus-insect cell expression system to prepare recombinant human CYP3A4 microsomes. Then, in vitro enzyme incubation systems were established and used UPLC-MS/MS to detect ketamine metabolite. In rats, we investigated the metabolism of ketamine and its metabolite in the presence of the CYP3A4 inhibitor voriconazole. Molecular docking was used to explore the molecular mechanism of inhibition. The results showed that the catalytic activity of CYP3A4.5, .17, .23, .28, and .29 significantly decreased compared to CYP3A4.1, with a minimum decrease of 3.13%. Meanwhile, the clearance rate of CYP3A4.2, .32, and .34 enhanced remarkably, ranging from 40.63% to 87.50%. Additionally, hepatic microsome incubation experiments revealed that the half-maximal inhibitory concentration (IC50) of voriconazole for ketamine in rat and human liver microsomes were 18.01 ± 1.20 µM and 14.34 ± 1.70 µM, respectively. When voriconazole and ketamine were co-administered, the blood exposure of ketamine and norketamine significantly increased in rats, as indicated by the area under the concentration-time curve (AUC) and maximum concentration (Cmax). The elimination half-life (t1/2Z) of these substances was also prolonged. Moreover, the clearance (CLz/F) of ketamine decreased, while the apparent volume of distribution (Vz/F) increased significantly. This might be attributed to the competition between voriconazole and ketamine for binding sites on the CYP3A4 enzyme. In conclusion, variations in CYP3A4 activity would result in the stratification of ketamine blood exposure.

Triazole-resistant Aspergillus luchuensis, an industrially important black Aspergillus spp. used in fermentation in East Asia, isolated from the patient with invasive pulmonary aspergillosis in China.

Aspergillus luchuensis, an industrially important member of Aspergillus species belonging to section Nigri used in fermentation in East Asia, was isolated from an immunocompromised patient with probable invasive pulmonary aspergillosis who failed voriconazole therapy in China. This isolate showed non-wild-type susceptibility to itraconazole, voriconazole, isavuconazole, and posaconazole. A G1378A mutation in cyp51A, resulting in the G441S amino acid substitution, which is the homolog to G448S conferring triazole-resistance in A. fumigatus, was detected in the A. luchuensis isolate.

Differential Functions of Individual Transcription Factor Binding Sites in the Tandem Repeats Found in Clinically Relevant cyp51A Promoters in Aspergillus fumigatus.

Aspergillus fumigatus is the major filamentous fungal pathogen in humans. The gold standard treatment of A. fumigatus is based on azole drug use, but the appearance of azole-resistant isolates is increasing at an alarming rate. The cyp51A gene encodes the enzymatic target of azole drugs, and azole-resistant alleles of cyp51A often have an unusual genetic structure containing a duplication of a 34- or 46-bp region in the promoter causing enhanced gene transcription. These tandem repeats are called TR34 and TR46 and produce duplicated binding sites for the SrbA and AtrR transcription factors. Using site-directed mutagenesis, we demonstrate that both the SrbA (sterol response element [SRE]) and AtrR binding sites (AtrR response element [ATRE]) are required for normal cyp51A gene expression. Loss of either the SRE or ATRE from the distal 34-bp repeat of the TR34 promoter (further 5' from the transcription start site) caused loss of expression of cyp51A and decreased voriconazole resistance. Surprisingly, loss of these same binding sites from the proximal 34- or 46-bp repeat led to increased cyp51A expression and voriconazole resistance. These data indicate that these duplicated regions in the cyp51A promoter function differently. Our findings suggest that the proximal 34- or 46-bp repeat in cyp51A recruits a corepressor that requires multiple factors to act while the distal repeat is free of this repression and provides the elevated cyp51A expression caused by these promoter duplications. IMPORTANCE Aspergillus fumigatus is the most common human filamentous fungal pathogen. Azole drugs are the current therapy of choice for A. fumigatus, but the prevalence of azole resistance is increasing. The main genetic alteration causing azole resistance is a change in the cyp51A gene, which encodes the target of these drugs. Azole-resistant cyp51A alleles routinely contain duplications in their promoter regions that cause increased gene transcription. Here, we demonstrate that clinical isolates containing a 34- or 46-bp duplication in the cyp51A promoter required the presence of the transcription factor-encoding atrR gene to exhibit elevated azole resistance. Eliminations of transcription factor binding sites in the cyp51A gene have differential actions on expression of the resulting mutant allele. These data dissect the molecular inputs to cyp51A transcription and reveal a complicated function of the promoter of this gene that is critical in azole resistance.

Inhibition of azole-resistant Aspergillus fumigatus biofilm at various formation stages by antifungal drugs, including olorofim.

OBJECTIVES: Interest in aspergillosis has increased over the past decades. An increase in the incidence of azole-resistant Aspergillus fumigatus strains has been reported; therefore, the need for novel therapeutic approaches is urgent. The formation of biofilms contributes to pathogen resistance. We investigated the biofilm formation capabilities of azole-resistant A. fumigatus and analysed the susceptibility of biofilms at various developmental stages to three antifungal agents. METHODS: Biofilm formation of 19 clinical A. fumigatus strains (3 azole-susceptible and 16 azole-resistant strains) was determined by crystal violet staining and by an XTT assay over a period of 48 h. We measured antibiofilm activity of voriconazole, amphotericin B and olorofim. These agents were added before adhesion, after adhesion, after germination and to mature fungal biofilm. Antibiofilm activity was assessed in an XTT assay and in confocal laser scan microscopy. Additionally, a growth-kinetic assay with planktonic A. fumigatus was performed. RESULTS: Each of the antifungal agents inhibited the metabolic activity of A. fumigatus biofilms when applied at early stages of biofilm formation. The mature biofilms were more resistant. Olorofim and voriconazole showed promising effects against A. fumigatus adhesion and germination, whereas the mature biofilm was not affected by treatment. In contrast, the biofilm of A. fumigatus showed amphotericin B susceptibility throughout the entire developmental process. The planktonic cells were susceptible to all three antifungal drug classes with an inhibition peak at 12 h after incubation. CONCLUSIONS: This is the first known study to demonstrate the antibiofilm activity of olorofim, voriconazole and amphotericin B against azole-resistant A. fumigatus.

Plausible drug interaction between cyclophosphamide and voriconazole via inhibition of CYP2B6.

The inhibitory activities of eight cytochrome P450 (CYP) isoenzymes for representative or suspected inhibitors of CYPs, including pesticides, were evaluated simultaneously using an in vitro cocktail incubation method to demonstrate the importance of systematic evaluation of CYP inhibitory risks in drug interaction (DI). Potent inhibition of CYP2B6 was noticeable for some azoles, including voriconazole. When voriconazole and cyclophosphamide were co-administered in mice, cyclophosphamide-induced alopecia and leukopenia were significantly suppressed by approximately 50% with increased blood concentrations of cyclophosphamide. The formation of an active metabolite of cyclophosphamide was suppressed effectively by voriconazole in the mouse liver microsomes. Surveys of adverse event reporting databases in Japan (JADER) and the U.S. (FAERS) showed that the proportional reporting ratios of neutropenia, hemorrhagic cystitis, and alopecia for cyclophosphamide, which is principally activated by CYP2B6 in humans, were mostly reduced, or tended to be reduced when azoles, including voriconazole, were prescribed in combination. It is highly likely that DIs between cyclophosphamide and azoles occur in the clinical setting. This study also suggests that more proper consideration of CYP2B6-mediated DIs is warranted. The combination of the in vitro cocktail method and a survey of adverse event reporting databases was a useful method to comprehensively detect pharmacokinetic DIs.

Nanosuspension as an Efficient Carrier for Improved Ocular Permeation of Voriconazole.

BACKGROUND: The present limitations related to the ocular administration of antifungal drugs for the treatment of fungal keratitis include poor ocular bioavailability, limited retention time, and low ocular tissue penetration. METHODS: This study aimed to prepare a novel ophthalmic voriconazole-loaded nanosuspension based on Eudragit RS 100. Pharmasolve® was explored as a corneal permeation enhancer in voriconazole ophthalmic formulation using in vitro and in vivo experiments. Briefly, 1% voriconazole-loaded nanosuspension was prepared using the quasi-emulsion solvent evaporation process. RESULTS: Characterizations of the voriconazole-loaded nanosuspension by Zetasizer Nano ZS and Transmission Electron Microscope (TEM) showed a uniform spherical shape without any agglomeration. The well-discreted nanoparticle with a size of 138 ± 1.3 nm was achieved with high entrapment efficiency (98.6 ± 2.5%) and positive zeta potential in the range of 22.5-31.2mV, indicating excellent physical stability. DISCUSSION: Voriconazole-loaded nanosuspension containing the penetration enhancer displayed good permeability both in vitro and in vivo compared with the commercial voriconazole injection. The voriconazole-loaded nanosuspension exhibited good antifungal activity, significantly inhibiting the growth of Candida albicans at a lower concentration of voriconazole (2.5µg/mL, p < 0.05). CONCLUSION: In conclusion, the voriconazole-loaded nanosuspension containing Pharmasolve® can be used as an effective ophthalmic formulation for the topical ocular delivery of voriconazole.

A Prospective Study on the Usefulness of Initial Voriconazole Dose Adjustment Based on CYP2C19 Gene Polymorphism Analysis.

Genetic polymorphism exists for CYP2C19, a dominant metabolic enzyme of voriconazole (VRCZ), and VRCZ pharmacokinetics has been shown to fluctuate according to the CYP2C19 phenotype. Although dosages for different phenotypes have been recommended in various retrospective studies, few reports have adjusted the initial VRCZ dose based on CYP2C19 phenotype determined prior to administration. In this study, we prospectively evaluated the usefulness of CYP2C19 polymorphism analysis in adjusting the initial VRCZ maintenance dose. The study enrolled 19 patients who underwent analysis of CYP2C19 polymorphism prior to VRCZ administration. Subjects were classified into 3 phenotype subgroups: extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM). The initial VRCZ maintenance doses given twice daily were proposed as follows: approximately 8, 6, and 4 mg/kg/day for EM, IM and PM, respectively, according to previous reports. In EM, the initial maintenance dose was 8.0 ± 0.5 mg/kg/day, and trough level was 6.6 ± 2.4 µg/mL. By contrast, the initial maintenance doses in IM and PM were 5.5 ± 0.7 and 4.1 ± 0.3 mg/kg/day, and the initial trough concentrations were 2.9 ± 1.2 and 2.6 ± 0.4 µg/mL, respectively. The attainment rate of target trough concentration of 1-6 µg/mL was 50% in EM, and was 100% in IM and PM. Determining the initial dose of VRCZ only by phenotype based on CYP2C19 gene polymorphism was found to be challenging. However, decreasing the initial maintenance dose in IM and PM may be important for adjusting the initial trough level to target range.

Oral absorption of voriconazole is affected by SLCO2B1 c.*396T>C genetic polymorphism in CYP2C19 poor metabolizers.

High pharmacokinetic variability of voriconazole is mainly explained by CYP2C19 phenotype, but there are still unknown factors affecting the variability. In this study, the effect of solute carrier organic anion transporter family member 2B1 (SLCO2B1) genotype on the pharmacokinetics (PKs) of voriconazole was evaluated in 12 healthy CYP2C19 poor metabolizers after a single administration of voriconazole 200 mg intravenously and orally. In addition, the influence of CYP3A4 enzyme activity was also explored. The oral absorption of voriconazole was decreased and delayed in the subjects with the SLCO2B1 c.*396T>C variant compared to the subjects with wild type. However, the CYP3A activity markers measured in this study did not show significant association with metabolism of voriconazole. The results suggest that the SLCO2B1 c.*396T>C may be associated with the decreased function of intestinal OATP2B1, and it could contribute to interindividual PK variability of voriconazole.

A Novel Study Design Using Continuous Intravenous and Intraduodenal Infusions of Midazolam and Voriconazole for Mechanistic Quantitative Assessment of Hepatic and Intestinal CYP3A Inhibition.

The extent of a drug-drug interaction (DDI) mediated by cytochrome P450 (CYP) 3A inhibitors is highly variable during a dosing interval, as it depends on the temporal course of victim and perpetrator drug concentrations at intestinal and hepatic CYP3A expression sites. Capturing the time course of inhibition is therefore difficult using standard DDI studies assessing changes in area under the curve; thus, a novel design was developed. In a 4-period changeover pilot study, 6 healthy men received intraduodenal or intravenous infusions of the CYP3A substrate midazolam (MDZ) at a rate of 0.26 mg/h for 24 hours. This was combined with intraduodenal or intravenous infusion of the CYP3A inhibitor voriconazole (VRZ), administered at rates of 7.5 mg/h from 8 to 16 hours and of 15 mg/h from 16 to 24 hours, after starting midazolam administration. Plasma and urine concentrations of VRZ, MDZ, and its major metabolites were quantified by liquid chromatography-tandem mass spectrometry and analyzed by semiphysiological population pharmacokinetic nonlinear mixed-effects modeling. A model including mechanism-based inactivation of the metabolizing enzymes (maximum inactivation rate constant kinact , 2.83 h-1 ; dissociation rate constant KI , 9.33 µM) described the pharmacokinetics of VRZ well. By introducing competitive inhibition by VRZ on primary and secondary MDZ metabolism, concentration-time profiles, MDZ and its metabolites were captured appropriately. The model provides estimates of local concentrations of substrate and inhibitor at the major CYP3A expression sites and thus of the respective dynamic extent of inhibition. A combination of intravenous and intraduodenal infusions of inhibitors and substrates has the potential to provide a more accurate assessment of DDIs occurring in both gut wall and liver.

Voriconazole-loaded self-nanoemulsifying drug delivery system (SNEDDS) to improve transcorneal permeability.

The aim of this study was to develop self- nanoemulsifying drug delivery system (SNEDDS) to improve the transcorneal permeability of voriconazole. A 'mixture design around a reference mixture' approach was applied. This latter included four components, namely, isopropyl myristate, PEG 400, Tween® 80 and Span® 80 as oil, co-solvent, surfactant and co-surfactant, respectively. Droplet size was selected as response. The effect of mixture components on droplet size was analyzed by means of response trace method. Optimal formulation was subjected to stability studies and characterized for droplet size, polydispersity index (PDI), pH, osmolarity, viscosity and percentage of transmittance. Ex-vivo transcorneal permeation of the optimal and the marketed formulations was carried out on excised bovine cornea using Franz cell diffusion apparatus. Optimal voriconazole loaded-SNEDDS showed moderate emulsification efficiency and was characterized by a droplet size of 21.447 ± 0.081 nm, a PDI of 0.156 ± 0.004, a pH of 7.205 ± 0.006, an osmolarity of 310 mosmol/Kg and a viscosity of 8.818 ± 0.076 cP. Moreover, it presented an excellent stability and exhibited a significant improvement (p < 0.05) in apparent permeability coefficient (1.982 ± 0.187 × 10-6 cm/s) when compared to commercialized formulation (1.165 ± 0.106 × 10-6 cm/s). These results suggest that SNEDDS is a promising carrier for voriconazole ocular delivery.

Iontophoresis enhances voriconazole antifungal potency and corneal penetration.

Strategies to enhance corneal penetration of voriconazole (VOR) could improve the treatment of fungal keratitis. Here, we evaluated the use of iontophoresis for ocular VOR delivery from either: (i) a cyclodextrin inclusion complex (CD VOR), (ii) a liposome (LP VOR), and (iii) a chitosan-coated liposome (LP VOR CS). LP VOR CS presented mean diameter of 139.2 ±â€¯1.3 nm and zeta potential equal to + 3.3 ±â€¯1.5 mV compared to 134.6 ±â€¯1.7 and -8.2 ±â€¯3.0 mV of LP VOR, which, together with mucin mucoadhesion study, confirmed chitosan-coating. Both drug and liposomal formulations were stable under the influence of an applied electric current. Interestingly, in vitro studies in Candida glabrata culture indicated a decrease in VOR MIC values following iontophoresis (from 0.28 to 0.14 µg/mL). Iontophoresis enhanced drug penetration into the cornea. After 10 min of a 2 mA/cm2 applied current, corneal retained amounts were 45.4 ±â€¯11.2, 30.4 ±â€¯2.1 and 30.6 ±â€¯2.9 µg/cm2 for, respectively, CD VOR, LP VOR, and LP VOR CS. In conclusion, iontophoresis increases drug potency and enhances drug penetration into the cornea, showing potential to be used as "an emergency burst delivery approach".

Effect of cyclosporine a and polymorphisms in CYP2C19 and ABCC2 on the concentration of voriconazole in patients undergoing allogeneic hematopoietic stem cell transplantation.

1. Voriconazole is known to display highly variable pharmacokinetics affecting treatment efficacy and safety. This study aimed to identify the factors causing the variation of voriconazole concentration in patients with allogeneic hematopoietic stem cell transplantation.2. The data of patients was collected, including clinical characteristics and voriconazole concentrations. A total of 5 single nucleotide polymorphisms of 3 candidate genes (CYP2C19, ABCC2, ABCG2) related to voriconazole metabolism were genotyped by MassArray method. The correlation between polymorphisms and voriconazole concentration was analyzed.3. A total of 244 voriconazole concentrations of 43 patients were included in this study. The voriconazole concentration was significantly correlated with patients' total bile acid (p = 0.001) and cyclosporin A (p < 0.001). The median concentration of the CYP2C19 normal metabolizers was remarkably lower than poor metabolizers (0.86 vs 2.27 µg/mL). The median concentration of ABCC2 rs2273697 GG genotype carriers was significantly higher than that of GA genotype carriers (p = 0.026).4. The variability of voriconazole concentration is partially explained by total bile acid, metabolic types of CYP2C19. The voriconazole concentration of CYP2C19 normal metabolizers is likely to be lower than 1.0 µg/mL and thus at risk of infection due to inadequate treatment.

Voriconazole-Based Salts Are Active against Multidrug-Resistant Human Pathogenic Yeasts.

Voriconazole (VOR) hydrochloride is unequivocally converted into VOR lactates and valinates upon reaction with silver salts of organic acids. This study found that the anticandidal in vitro activity of these compounds was comparable or slightly better than that of VOR. The Candida albicans clinical isolate overexpressing CaCDR1/CaCDR2 genes, highly resistant to VOR, was apparently more susceptible to VOR salts. On the other hand, the susceptibility of another C. albicans clinical isolate (demonstrating multidrug resistance due to the overexpression of CaMDR1) to VOR salts was comparable to that to VOR. Comparative studies on the influence of VOR and its salts on Rhodamine 6G efflux from susceptible and multidrug-resistant C. albicans cells revealed that VOR salts are poorer substrates for the CaCdr1p drug efflux pump than VOR.

Novel insights into the complex pharmacokinetics of voriconazole: a review of its metabolism.

Voriconazole, a second-generation triazole frequently used for the prophylaxis and treatment of invasive fungal infections, undergoes complex metabolism mainly involving various (polymorphic) cytochrome P450 enzymes in humans. Although high inter- and intraindividual variability in voriconazole pharmacokinetics have been observed and the therapeutic range for this compound is relatively narrow, the metabolism of voriconazole has not been fully elucidated yet. The available literature data investigating the multiple different pathways and metabolites are extremely unbalanced and thus the absolute or relative contribution of the different pathways and enzymes involved in the metabolism of voriconazole remains uncertain. Furthermore, other factors such as nonlinear pharmacokinetics caused by auto-inhibition or -induction and polymorphisms of the metabolizing enzymes hinder safe and effective voriconazole dosing in clinical practice and have not yet been studied sufficiently. This review aimed at amalgamating the available literature on the pharmacokinetics of voriconazole in vitro and in vivo, with a special focus on metabolism in adults and children, in order to congregate an overall landscape of the current body of knowledge and identify knowledge gaps, opening the way towards further research in order to foster the understanding, towards better therapeutic dosing decisions.

The challenges of treating aspergillus abdominal aneurysm after hematopoietic cell transplant: Rapid voriconazole metabolizer.

Mycotic aneurysms are a fatal manifestation of disseminated fungal infections in immunocompromised hosts. We present a patient with an Aspergillus mycotic aneurysm after hematopoietic cell transplant. Due to CYP2C19 rapid metabolizer phenotype (*1/*17), therapeutic levels of voriconazole were unobtainable. Successful therapy was achieved with posaconazole salvage therapy and early, aggressive surgery. This case demonstrates the consequences of voriconazole rapid metabolism and the potential impact of genetic variants.

The impact of proton pump inhibitors on the pharmacokinetics of voriconazole in vitro and in vivo.

Voriconazole (VRC) and proton pump inhibitors (PPIs) have similar metabolic pathways. The objectives of the study are to evaluate the impact of PPIs on the pharmacokinetics of VRC. Human liver microsomes model was applied to assess the inhibitory effects of PPIs on the metabolism of VRC in vitro. A retrospective study was also carried out to explore the relationship between the plasma VRC trough concentrations and PPIs uses. Patients were divided into six groups: control (n = 166), lansoprazole (LAN, n = 38), esomeprazole (ESO, n = 19), omeprazole (OME, n = 45), pantoprazole (PAN, n = 43), and ilaprazole (ILA, n = 38) groups. All five PPIs showed concentration-dependent inhibitory effects on the VRC metabolism in human liver microsomes, among which LAN, OME and ESO were three of the most potent inhibitors. Consistently, co-administered with LAN, OME and ESO significantly increased the plasma VRC trough levels (p < 0.05), whereas there was no significant association between VRC concentrations and PAN or ILA use. Interestingly, patients in the PPIs groups were more likely to reach the therapeutic VRC range of 1-5.5 µg/mL in steady state when compared with control patients (75-81% VS 69%). In conclusion, although all PPIs showed inhibitory effects on the VRC metabolism in vitro, only LAN, OME and ESO significantly increased VRC plasma concentrations. This study should be helpful for choice of the type of PPIs for patients administered with VRC.

Photosensitisation by voriconazole-N-oxide results from a sequence of solvent and pH-dependent photochemical and thermal reactions.

The phototoxicity of voriconazole (VN) prescribed in the treatment of severe fungal infections is frequently reported. Its major metabolite, a N-oxide derivative (VNO), was suspected to be the photosensitizer because it shows a maximum absorbance at ~310 nm in aqueous solutions. It was reported that the VNO photoproduct (VNOP) was phototoxic to human keratinocytes. Steady state and laser flash photolyses were performed to shed light on the phototoxic properties of VNO and VNOP. The quantum yield of the VNOP production by UVB-UVA light in buffered or alcoholic solutions is 0.6. VNOP has been identified as (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-7-oxa-1,3-diazabicyclo[4.1.0]hepta-2,4-dien-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol. VNOP undergoes a marked thermal degradation and an efficient UVA photolysis with well differentiated kinetics and end-products. The temperature-dependent VNOP dark degradation produces a single product VNOPD identified as 6-[(2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-5-fluoropyrimidin-4-ol with absorbance maximum at 308 nm and ε = 2700 M-1 cm-1. Under UVB-UVA irradiation, VNOPD, the stable end-product, is a remarkable photodynamic photosensitizer towards Trp and His. The Trp photo-oxidation (Φox(Trp) = 0.13) mainly involves type I radical reactions whereas His is oxidized by 1O2 (Φox(His) = 0.012). These results force us to question the validity of the in vitro photosensitization of human keratinocytes by VNO and VNOP previously reported.

Tissue Distribution and Elimination of Isavuconazole following Single and Repeat Oral-Dose Administration of Isavuconazonium Sulfate to Rats.

Quantitative whole-body autoradiography was used to assess the distribution and tissue penetration of isavuconazole in rats following single and repeated oral-dose administration of radiolabeled isavuconazonium sulfate, the prodrug of isavuconazole. Following a single-dose administration of radiolabeled isavuconazonium sulfate (labeled on the active moiety), radioactivity was detectable within 1 h postdose in 56 of 65 tissue/fluid specimens. The highest maximum concentrations (Cmax) were observed in bile and liver (66.6 and 24.7 µg eq/g, respectively). The lowest Cmax values were in bone and eye lens (0.070 and 0.077 µg eq/g, respectively). By 144 h postdose, radioactivity was undetectable in all tissues/fluids except liver (undetectable at 336 h) and adrenal gland tissues (undetectable at 672 h). Following daily administration for up to 21 days, 1-h-postdose Cmax values were the highest on or before day 14 in all except seven tissues/fluids, of which only rectum mucosa and small intestine mucosa had Cmax values >25% higher than all other 1-h-postdose values. For 24-h-postdose Cmax values, only large intestine, large intestine mucosa, and urine had the highest Cmax values at day 21. The penetration of single oral doses of unlabeled isavuconazole (25 mg/kg of body weight isavuconazonium sulfate) and voriconazole (50 mg/kg) into rat brain (assessed using liquid chromatography-tandem mass spectrometry) was also compared. Brain concentration/plasma concentration ratios reached approximately 1.8:1 and 2:1, respectively. These data suggest that isavuconazole penetrates most tissues rapidly, reaches a steady state in most or all tissues/fluids within 14 days, does not accumulate in tissues/fluids over time, and achieves potentially efficacious concentrations in the brain.

Observational Study of Associations between Voriconazole Therapeutic Drug Monitoring, Toxicity, and Outcome in Liver Transplant Patients.

The aim of this study was to investigate the variability of the voriconazole plasma level and its relationships with clinical outcomes and adverse events among liver transplant recipients to optimize the efficacy and safety of their treatment. Liver transplant recipients treated with voriconazole were included, and voriconazole trough levels were quantified by a validated high-performance liquid chromatography method. Cytochrome P450 genotypes for CYP2C19 were evaluated in allograft liver tissues. A total of 832 voriconazole trough levels from 104 patients were measured. Proven, probable, and possible invasive fungal infections were reported for 8/104 (7.7%), 42/104 (40.4%), and 54/104 (51.9%) patients, respectively. Receiver operating characteristic (ROC) curve analysis indicated that trough concentrations of ≥1.3 µg/ml minimized the incidence of treatment failure (95% confidence interval [CI], 0.68 to 0.91 µg/ml) (P < 0.001) and that those of <5.3 µg/ml minimized the incidence of any adverse events (95% CI, 0.83 to 0.97 µg/ml) (P < 0.001). Voriconazole trough levels were significantly higher for heterozygous extensive metabolizers, poor metabolizers, and individuals receiving coadministration with proton pump inhibitors. For ultrarapid metabolizers, oral administration of voriconazole, and concomitant use of glucocorticoids, voriconazole blood concentrations were significantly reduced. Furthermore, there was no statistically significant association of patient age, weight, or gender or coadministration of tacrolimus and cyclosporine with the voriconazole trough level. In conclusion, the results of our analysis indicate large inter- and intraindividual variabilities of voriconazole concentrations in liver transplant recipients. Voriconazole trough concentrations of ≥1.3 µg/ml and <5.3 µg/ml are optimal for treatment and for minimization of adverse events. Optimization of drug efficacy and safety requires the use of rational doses for voriconazole therapy.

Comparison of Oral Voriconazole Versus Oral Ketoconazole as an Adjunct to Topical Natamycin in Severe Fungal Keratitis: A Randomized Controlled Trial.

PURPOSE: To compare the efficacy of oral voriconazole (VCZ) with oral ketoconazole (KCZ) as an adjunct to topical natamycin in severe fungal keratitis. METHODS: Fifty eyes of 50 patients with proven severe fungal keratitis, (>5 mm size, involving >4 mm central cornea and >50% stromal depth), smear, and/or culture positive were randomized to receive either oral VCZ (n = 25) or oral KCZ (n = 25) 200 mg twice a day. Both groups received topical natamycin along with oral medication. The primary outcome measure was best spectacle-corrected visual acuity (BSCVA) at 3 months of follow-up. Secondary outcomes were the percentage of healed cases and scar size. RESULTS: The mean BSCVA after treatment was 1.3 ± 0.35 logarithm of minimum angle of resolution units in the VCZ group and 1.6 ± 0.39 logarithm of minimum angle of resolution units in the KCZ group [P = 0.004, 95% confidence interval (CI), -0.10 to 0.54]. The final mean scar size was smaller for oral VCZ than for oral KCZ (P = 0.04, 95% CI, -0.01 to 0.93 mm). The percentage of cases healed were 80% and 72% in VCZ and KCZ groups, respectively (P = 0.51, 95% CI, -0.15 to 0.31). The ratio of tear film to serum concentration of oral VCZ was better than oral KCZ at days 14 (P = 0.002) and 21 (P = 0.006). CONCLUSIONS: Although the duration and percentage of healing was similar in both groups, oral VCZ attained a significantly better tear film concentration with a smaller scar size and better BSCVA compared with oral KCZ. Thus, oral VCZ may be preferred over oral KCZ in severe fungal keratitis.