Voriconazole Dose Research Articles

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Introduction: Oral voriconazole is recommended over intravenous (IV) voriconazole in patients with CrCl < 50 ml/min to avoid accumulation of SBECD; however, poor enteral absorption in ICU patients may lead to inadequate plasma concentrations and treatment failure. The purpose of this study was to evaluate the pharmacokinetics of SBECD and IV voriconazole in ICU patients undergoing CRRT. Hypothesis: CRRT is effective at removing SBECD and allows use of IV voriconazole without concern of SBECD accumulation. Methods: Patients > 18 years of age receiving IV voriconazole therapy for treatment or prophylaxis of systemic fungal infection while undergoing CRRT were eligible. Intensive pharmacokinetic sampling for determination of SBECD and voriconazole concentrations was completed on study days 1, 3, and 5; then sparse sampling every 3-5 days thereafter. Voriconazole and SBECD plasma and effluent concentrations were measured by LC MS/MS. Results: Six patients were enrolled. Patients were (mean ± SD) 56 ± 11 years old, 67% male, 83 ± 12 kg, and had APACHE II scores of 30.5 ± 3.3. All patients received CVVH with a median predilution replacement fluid rate of 36 (IQR 32-39) ml/kg/hr and effluent rate of 38 (IQR 35-40) ml/kg/hr. Mean ± SD voriconazole and SBECD dosages administered were 7.9 ± 2.6 mg/kg/day and 126 ± 42 mg/kg/day. Mean ± SD plasma voriconazole Cmax, Cmin, Vd, t1/2, AUC0-12, total systemic clearance, and CRRT clearance were 3.6 ± 1.6 mg/L, 1.6 ± 0.8 mg/L, 2.8 ± 0.6 L/kg, 15 ± 7 hrs, 29 ± 10 mg*hr/L, 0.15 ± 0.05 L/hr/kg, and 0.03 ± 0.03 L/hr/kg, respectively. Mean ± SD plasma SBECD Cmax, Cmin, Vd, t1/2, AUC0-12, total systemic clearance, and CRRT clearance were 276 ± 154 mg/L, 55 ± 47 mg/L, 0.5 ± 0.2 L/kg, 6.6 ± 2.4 hrs, 1600 ± 1000 mg*hr/L, 0.05 ± 0.02 L/hr/kg, and 0.03 ± 0.01 L/hr/kg, respectively. Minimal increases in SBECD Cmax (255 ± 143 to 331 ± 255 mg/L; p=0.54) and Cmin (64 ± 59 to 76 ± 64 mg/L; p=0.74) were observed after study day 1. Conclusions: CVVH effectively removed SBECD at a rate similar to the effluent rate. Voriconazole clearance by CVVH was not clinically significant. Standard dosages of IV voriconazole can be utilized in patients undergoing CVVH without significant risk of SBECD accumulation.

Voriconazole hepatotoxicity in severe liver dysfunction

There are no studies regarding to these effects in patients with severe liver dysfunction. The aims of this study were to characterize voriconazole hepatotoxicity in patients with severe liver dysfunction and to compare it with a matched cohort treated with liposomal amphotericin B. This is an observational study, in which adults patients treated with at least 4 doses of voriconazole were included. Patients treated with liposomal amphotericin B were used as control group. Sixty nine percent of patients treated with voriconazole showed changes in liver function tests (LFTs) during therapy. They showed elevated transaminases in 35%, cholestasis in 15% or a combination of both in 45%. According to the CTC classification, all patients with hepatotoxicity had a severe reaction. The Roussel Uclaf Causality Assessment Method score in all patients with hepatotoxicity was greater than 8. There was a correlation between initial loading dose greater than 300 mg (4.5 mg/kg) and the risk of hepatotoxicity (p < 0.001). The control group developed alterations in the LFTs in only 10.3% of patients. Voriconazole should be used with caution in patients with severe liver dysfunction and following liver transplantation, with frequent monitoring of LFTs or using liposomal amphotericin B instead.

Effect of PTX3 and Voriconazole Combination in a Rat Model of Invasive Pulmonary Aspergillosis

This study evaluated the pharmacological activity of PTX3, administered in combination with voriconazole, in a rat model of pulmonary aspergillosis. The data indicated additive therapeutic activities of these compounds, as demonstrated by the amelioration of respiratory function changes, reduction of lung fungal burden, and increased survival. Overall, we provide clear evidence that the combination of PTX3 with a suboptimal dose of voriconazole might represent a therapeutic option under those clinical conditions where the use of voriconazole alone is not warranted for efficacy and tolerability reasons.

SUCCESSFUL TREATMENT OF A SEVERE CASE OF FUSARIOMYCOSIS IN A BELUGA WHALE (DELPHINAPTERUS LEUCAS LEUCAS)

An adult male beluga whale (Delphinapterus leucas leucas) was presented with a 4-cm-diameter, raised, firm nodule on the medial aspect of the left pectoral fin. A fissure developed within the center of the nodule, which formed an ulcerated cyst-like lesion. The lesion rapidly progressed in size, and, with peeling of material present within the cyst, the lesion flattened to a 36 x 25-cm cutaneous ulcer that extended into the axilla. Histopathologic features were consistent with lymphocytic and suppurative dermatitis with intralesional fungi. Fusarium solani was diagnosed by polymerase chain reaction (PCR). Fungal susceptibility testing was performed and revealed drug resistance to multiple antifungal medications tested individually and in combination therapies. Treatments used included serial surgical debridement of affected and surrounding tissue, topical application and regional infusion of various azole, and allylamine antifungals combined with either dimethyl sulfoxide or Tricide for absorption potentiation, and oral voriconazole administration. Although susceptibility testing revealed resistance to voriconazole, visible improvement of the lesion was noted after 6 weeks of oral voriconazole therapy. The voriconazole dosage was tapered based on serum levels and was administered over a 12-mo period. No local recurrence or new lesions were visible by 14 mo from first presentation.

Importance of voriconazole therapeutic drug monitoring in pediatric cancer patients with invasive aspergillosis

Voriconazole is the drug of choice for invasive aspergillosis (IA) and drug levels are influenced by interactions with other drugs and genetic predisposition. We performed a retrospective analysis of voriconazole drug levels and investigated the adequacy of drug levels in pediatric cancer patients and hematopoietic cell transplant (HCT) recipients with IA. Trough serum concentrations of voriconazole in patients younger than 19 years during a 30-month period were analyzed. The therapeutic range was determined as 1-6 µg/ml. A total of 193 voriconazole measurements at steady-state [86 on intravenous (IV) and 107 on oral (PO) doses] were obtained from 27 patients (median age 12.2 years). On the first monitoring, 19 patients (70.4%) achieved the therapeutic range. However, only 10 patients (37.0%) achieved the therapeutic range on second monitoring. Sixty-four percent of the total measurements were within the therapeutic range: 66.3% of IV and 61.7% of PO. A significant correlation between oral doses and trough levels of voriconazole was observed in patients ≤6 years old (Spearman's rank correlation coefficient = 0.4819, P = 0.027). Patients aged ≤6 years needed a significantly higher median dose of PO voriconazole to maintain therapeutic trough levels compared to older patient groups (8.9 vs. 4.2 mg/kg/dose, P < 0.001). Voriconazole level <1 µg/ml was more frequently observed in patients with treatment failure at week 6 of voriconazole therapy (failure vs. success, 42.1% vs. 19.7%; P = 0.012). Serum concentrations of voriconazole in children were variable, depending on the patient's age and route of administration. Continuous and careful drug level monitoring should be performed.

In Vitro Pharmacokinetic/Pharmacodynamic Modeling of Voriconazole Activity against Aspergillus Species in a New In Vitro Dynamic Model

The pharmacodynamics (PD) of voriconazole activity against Aspergillus spp. were studied using a new in vitro dynamic model simulating voriconazole human pharmacokinetics (PK), and the PK-PD data were bridged with human drug exposure to assess the percent target (near-maximum activity) attainment of different voriconazole dosages. Three Aspergillus clinical isolates (1 A. fumigatus, 1 A. flavus, and 1 A. terreus isolate) with CLSI MICs of 0.5 mg/liter were tested in an in vitro model simulating voriconazole PK in human plasma with C(max) values of 7, 3.5, and 1.75 mg/liter and a t(1/2) of 6 h. The area under the galactomannan index-time curve (AUC(GI)) was used as the PD parameter. In vitro PK-PD data were bridged with population human PK of voriconazole exposure, and the percent target attainment was calculated. The in vitro PK-PD relationship of fAUC(0-24)-AUC(GI) followed a sigmoid pattern (global R(2) = 0.97), with near-maximum activities (10% fungal growth) observed at an fAUC(0-24) (95% confidence interval [CI]) of 18.9 (14.4 to 23.1) mg · h/liter against A. fumigatus, 26.6 (21.1 to 32.9) mg · h/liter against A. flavus, and 36.2 (27.8 to 45.7) mg · h/liter against A. terreus (F test; P < 0.0001). Target attainment for 3, 4, and 5 mg/kg-of-body-weight voriconazole dosages was 24% (11 to 45%), 80% (32 to 97%), and 93% (86 to 97%) for A. fumigatus, 12% (5 to 26%), 63% (17 to 93%), and 86% (73 to 94%) for A. flavus, and 4% (2 to 11%), 36% (6 to 83%), and 68% (47 to 83%) for A. terreus. Based on the in vitro exposure-effect relationships, a standard dosage of voriconazole may be adequate for most patients with A. fumigatus but not A. flavus and A. terreus infections, for which a higher drug exposure may be required. This could be achieved using a higher voriconazole dosage, thus highlighting the usefulness of therapeutic drug monitoring in patients receiving a standard dosage.

Voriconazole Is Delivered From Antifungal-Loaded Bone Cement

Local delivery of antifungals is an important modality in managing orthopaedic fungal infection. Voriconazole is a powder antifungal suitable for addition to bone cement that is released from bone cement but the mechanical properties of antimicrobial-loaded bone cement (ALBC) made with voriconazole are unknown. (1) Is voriconazole release dose-dependent? (2) Is released voriconazole active? (3) Is the loss of ALBC's compressive strength caused by voriconazole dose- and elution-dependent? Sixty standard test cylinders were fabricated with ALBC: 300 or 600mg voriconazole per batch eluted for 30days in deionized water. Voriconizole concentration in the eluate was measured using high-performance liquid chromatography. Cumulative-released voriconizole was calculated. Biologic activity was tested. Compressive strength was measured before and after elution. The effect of dose and time on release and compressive strength were analyzed using repeated-measure analysis of variance. Fifty-seven percent and 63% of the loaded voriconazole were released by Day 30 for the 300-mg and 600-mg formulations, respectively. The released voriconazole was active on bioassay. Compressive strength was reduced from 79MPa to 53MPa and 69MPa to 31MPa by 30days for the 300-mg and 600-mg formulations, respectively. Voriconazole release from ALBC increases with dose and is bioactive. Loss in compressive strength is greater after elution and with higher dose. Three hundred milligrams of voriconazole in ALBC would be expected to deliver meaningful amounts of active drug in vivo. The compressive strength of ALBC with 600mg voriconazole is less than expected compared to commonly used antibacterials.

The Effect of Therapeutic Drug Monitoring on Safety and Efficacy of Voriconazole in Invasive Fungal Infections: A Randomized Controlled Trial

Blood levels of voriconazole, a first line therapy for invasive aspergillosis, may correlate with adverse events and treatment response. However, no randomized controlled studies have been conducted to evaluate the clinical utility of routine therapeutic drug monitoring (TDM) of voriconazole. This study aimed to determine whether routine TDM of voriconazole reduces drug adverse events or improves treatment response in invasive fungal infections. This was a randomized, assessor-blinded, controlled, single center trial. One hundred ten adult patients were randomly assigned to TDM or non-TDM groups. In the TDM group, voriconazole dosage was adjusted (target range, 1.0-5.5 mg/L) according to the serum trough level measured on the fourth day after initiation of voriconazole. The non-TDM group received a fixed, standard dosage. Voriconazole-related adverse events were monitored, and treatment response was assessed three months after the initiation of therapy. Baseline characteristics including the CYP2C19 genotype were comparable between the two groups. While the incidence of adverse events was not different between the TDM group and the non-TDM group (both 42%; P = .97), the proportion of voriconazole discontinuation due to adverse events was significantly lower in the TDM group than in the non-TDM group (4% vs 17%; P = .02). A complete or partial response was observed in 81% (30 of 37) of patients in the TDM group compared to 57% (20 of 34) in the non-TDM group (P = .04). Routine TDM of voriconazole may reduce drug discontinuation due to adverse events and improve the treatment response in invasive fungal infections. NCT00890708.

Voriconazole-induced Phototoxicity in Children

Voriconazole is used in antifungal prophylaxis. We performed a retrospective review of immunocompromised children receiving prophylaxis with voriconazole during major hospital renovation, who developed phototoxic skin reactions. The overall incidence of phototoxic skin reactions was 33%. A voriconazole dose of ≥6 mg/kg of body weight per dose twice daily was associated with a significantly greater risk to develop phototoxic skin reactions compared with lower doses.

Challenging Recommended Oral and Intravenous Voriconazole Doses for Improved Efficacy and Safety: Population Pharmacokinetics–Based Analysis of Adult Patients With Invasive Fungal Infections

Recommended oral voriconazole (VRC) doses are lower than intravenous doses. Because plasma concentrations impact efficacy and safety of therapy, optimizing individual drug exposure may improve these outcomes. A population pharmacokinetic analysis (NONMEM) was performed on 505 plasma concentration measurements involving 55 patients with invasive mycoses who received recommended VRC doses. A 1-compartment model with first-order absorption and elimination best fitted the data. VRC clearance was 5.2 L/h, the volume of distribution was 92 L, the absorption rate constant was 1.1 hour(-1), and oral bioavailability was 0.63. Severe cholestasis decreased VRC elimination by 52%. A large interpatient variability was observed on clearance (coefficient of variation [CV], 40%) and bioavailability (CV 84%), and an interoccasion variability was observed on bioavailability (CV, 93%). Lack of response to therapy occurred in 12 of 55 patients (22%), and grade 3 neurotoxicity occurred in 5 of 55 patients (9%). A logistic multivariate regression analysis revealed an independent association between VRC trough concentrations and probability of response or neurotoxicity by identifying a therapeutic range of 1.5 mg/L (>85% probability of response) to 4.5 mg/L (<15% probability of neurotoxicity). Population-based simulations with the recommended 200 mg oral or 300 mg intravenous twice-daily regimens predicted probabilities of 49% and 87%, respectively, for achievement of 1.5 mg/L and of 8% and 37%, respectively, for achievement of 4.5 mg/L. With 300-400 mg twice-daily oral doses and 200-300 mg twice-daily intravenous doses, the predicted probabilities of achieving the lower target concentration were 68%-78% for the oral regimen and 70%-87% for the intravenous regimen, and the predicted probabilities of achieving the upper target concentration were 19%-29% for the oral regimen and 18%-37% for the intravenous regimen. Higher oral than intravenous VRC doses, followed by individualized adjustments based on measured plasma concentrations, improve achievement of the therapeutic target that maximizes the probability of therapeutic response and minimizes the probability of neurotoxicity. These findings challenge dose recommendations for VRC.

Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia

Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia

Monitoring trough voriconazole plasma concentrations in haematological patients: real life multicentre experience

The objective of this retrospective study was to evaluate results from voriconazole therapeutic drug monitoring (TDM) in haematological patients in routine clinical practice. Between 2005 and 2010, 1228 blood samples were obtained from 264 haematological patients (median 3 samples/patient; range 1-27) receiving voriconazole for targeted/preemptive treatment of invasive aspergillosis (IA) (46.3% of samples), empirical therapy (12.9%) or prophylaxis (40.8%). A high-pressure liquid chromatography assay was used to analyse voriconazole concentrations. Clinical and laboratory data were analysed retrospectively. The median of the detected voriconazole plasma concentration was 1.00 μg ml(-1) (range <0.20-13.47 μg ml(-1)). Significant inter- and intra-patients variability of measured concentrations (81.9% and 50.5%) were identified. With the exception of omeprazole administration, there was no relevant relationship between measured voriconazole concentrations and drug dose, route administration, age, gender, CYP2C19*2 genotype, gastrointestinal tract abnormality, administration via nasogastric tube, serum creatinine, and liver enzymes. However, per patient analysis identified significant role of individual voriconazole dose and drug form change on measured plasma concentration. Measured voriconazole concentrations did not correlate with the treatment outcome of patients with IA. We only identified a limited number of adverse events related to voriconazole therapy; however, the median plasma concentration was not different from concentrations measured in samples without reported toxicity. Our retrospective study has suggested that routine monitoring of voriconazole plasma concentrations has probably only a limited role in daily haematological practice.

Integrated Population Pharmacokinetic Analysis of Voriconazole in Children, Adolescents, and Adults

To further optimize the voriconazole dosing in the pediatric population, a population pharmacokinetic analysis was conducted on pooled data from 112 immunocompromised children (2 to <12 years), 26 immunocompromised adolescents (12 to <17 years), and 35 healthy adults. Different maintenance doses (i.e., 3, 4, 6, 7, and 8 mg/kg of body weight intravenously [i.v.] every 12 h [q12h]; 4 mg/kg, 6 mg/kg, and 200 mg orally q12h) were evaluated in these children. The adult dosing regimens (6 mg/kg i.v. q12h on day 1, followed by 4 mg/kg i.v. q12h, and 300 mg orally q12h) were evaluated in the adolescents. A two-compartment model with first-order absorption and mixed linear and nonlinear (Michaelis-Menten) elimination adequately described the voriconazole data. Larger interindividual variability was observed in pediatric subjects than in adults. Deterministic simulations based on individual parameter estimates from the final model revealed the following. The predicted total exposure (area under the concentration-time curve from 0 to 12 h [AUC(0-12)]) in children following a 9-mg/kg i.v. loading dose was comparable to that in adults following a 6-mg/kg i.v. loading dose. The predicted AUC(0-12)s in children following 4 and 8 mg/kg i.v. q12h were comparable to those in adults following 3 and 4 mg/kg i.v. q12h, respectively. The predicted AUC(0-12) in children following 9 mg/kg (maximum, 350 mg) orally q12h was comparable to that in adults following 200 mg orally q12h. To achieve voriconazole exposures comparable to those of adults, dosing in 12- to 14-year-old adolescents depends on their weight: they should be dosed like children if their weight is <50 kg and dosed like adults if their weight is ≥ 50 kg. Other adolescents should be dosed like adults.

High frequency of voriconazole-related phototoxicity in cystic fibrosis patients

To the Editors: Aspergillus fumigatus infection is common in cystic fibrosis (CF) patients and estimates of the rate of allergic bronchopulmonary aspergillosis range from 1–15%. Voriconazole, a new triazole antifungal, has been recognised as efficient and safe in the treatment of invasive aspergillosis [1–2]. Since it is available orally, voriconazole became the first alternative to itraconazole. We began giving voriconazole to CF patients in 2003, and we encountered an unexpectedly high frequency of moderate-to-severe skin reactions, which limited the administration of the drug. We therefore reviewed all the medical files of children (aged <18 yrs; n=72) and adults (n=63) followed up in our tertiary CF reference centre between April 2003 and December 2008, in order to estimate the frequency of voriconazole-induced photosensitivity, as previously defined [3]. All the patients who were given voraconazole were selected. Demographic data, cystic fibrosis transmembrane conductance regulator (CFTR) mutations, clinical data, treatment, duration and voriconazole dosage, and related adverse effects (AEs) were collected. Qualitative and quantitative comparisons were analysed using the Chi-squared test and nonparametric Mann–Whitney test, respectively. Multivariate analyses were performed by using stepwise logistic regression. A p-value <0.05 was considered statistically significant. Statistical analyses were performed using Statistica 8 (StatSoft, Maisons-Alfort, France). 31 (21.4%) out of the 135 CF patients were given voriconazole. Their characteristics are described in table 1. When genotypes were categorised into CFTR mutation classes, 36.5% and 58%, respectively, were heterozygous and homozygous for class II mutations, which alter the maturation of CFTR protein. Voriconazole-related AEs were reported in 19 (61%) …

Prophylactic efficacy of single dose pulmonary administration of amphotericin B inhalation powder in a guinea pig model of invasive pulmonary aspergillosis

Amphotericin B inhalation powder (ABIP) is a novel dry-powder amphotericin B formulation that is directly delivered to the lung, resulting in elevated lung tissue drug concentrations of this polyene. We evaluated the prophylactic efficacy of single dose administration of ABIP in a guinea pig model of invasive pulmonary aspergillosis. Guinea pigs were immunosuppressed with cyclophosphamide and cortisone acetate and challenged with Aspergillus fumigatus conidia in an aerosol chamber. Guinea pigs received prophylaxis with a single inhaled dose of ABIP at 0.05, 0.5, 4 or 10 mg/kg administered 24 h prior to infection. Treatment with oral voriconazole at doses of 5 or 10 mg/kg twice daily beginning 24 h post-challenge served as the positive control. Improvements in survival were observed with ABIP prophylaxis. A single inhaled dose of 4 mg/kg ABIP and treatment with 5 mg/kg voriconazole both improved median and percentage survival compared with untreated controls. In addition, pulmonary fungal burden, as assessed by cfu, quantitative PCR and galactomannan, was also reduced in a dose-dependent fashion with ABIP prophylaxis as well as with both doses of voriconazole treatment. Single-dose prophylaxis with inhaled ABIP as prophylaxis demonstrated a significant survival advantage and reductions in pulmonary fungal burden in this model of invasive pulmonary aspergillosis. Optimization of the dose and dosing frequency of ABIP dose may help to further enhance the anti-Aspergillus activity of this novel amphotericin B formulation.

Highly Variable Plasma Concentrations of Voriconazole in Children Undergoing HSCT: Therapeutic Drug Monitoring (TDM) Is Indispensable

Invasive fungal infections are of great concern in pediatric HSCT recipients. Voriconazole is an important drug both for prophylaxis as well as for therapy. Optimum trough levels are between 1-5 mg/l. It is unclear whether these levels are reached with current pediatric dosing schedules. We retrospectively analysed the use of voriconazole in our unit between 2007 and 2011. 92 children between 0-19 years of age underwent HSCT. 57 of them (64%) were treated with voriconazole. 21% of them were <2 yrs, 47% 2-12-yrs and 32 % >12 yrs. Voriconazole was given as prophylaxis in 44% of cases, 23% received it empirically and 33% as therapy. 14 of the 19 children treated therapeutically had aspergillosis (11 possible, 2 probable, 1 proven). Dosing was according to the summary of product characteristics. For children < 2 yrs the recommended dosage for 2-12 yrs was used. Voriconazole was prescribed for a mean period of 63 days (range 6-415). In 11% of cases the drug was stopped due to toxicity. An adequate trough level was defined as 1-5 mg/ml. First measurement of trough levels was after a median of 5 days. Only in 8% of children < 2 years an adequate level was reached at initial dosing. 3 of 15 children between 2-7 yrs of age on recommended dosage had adequate levels at initial dosing (20%); in children aged 7-12 yrs 83% had adequate initial levels if dosage was as recommended. 14/33 patients >2 yrs on recommended dose had voriconazole levels below the limit of detection (<0.5 mg/ml). 9% of all patients had an initial trough level > 5 mg/ml. The mean dose (range) to reach adequate trough levels for children <2 was: 365 mg oral (220-600) and 29.4 mg/kg i.v. (5.2-70). For the age group 2-7 years adequate levels were reached with a mean dose of 26.2 mg/kg i.v. (20.7-29.6). >12 years this was 17.6 mg/kg i.v. (11.9-19.6). Intrapatient variability of levels on constant dosage was 0.7-3.5 fold. We conclude that therapeutic drug monitoring is indispensable for correct dosage of voriconazole. Dosage recommendations for children need adjustment, especially in the <2 age group. Intra patient variability is also a major concern and necesittates continued level measurements. Patient characteristics that determine pharmacokinetic variability need to be identified in future studies.

Voriconazole drug monitoring in the management of invasive fungal infection in immunocompromised children: a prospective study

To evaluate voriconazole plasma level monitoring in immunocompromised children and determine the relationship of plasma levels with dose, safety and efficacy. We used a prospective study including all consecutive children with invasive fungal infection (IFI) treated with voriconazole between August 2008 and May 2010. IFI diagnosis and clinical outcome evaluation were based on European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group ('EORTC/MSG') definitions. A total of 196 voriconazole plasma trough measurements from 30 patients (median age 10 years) obtained during 2135 days of voriconazole therapy were analysed. Nineteen patients (63%) presented with proven or probable IFI. Voriconazole plasma levels varied widely and 73% of patients required dose adjustment. The median voriconazole dose was 20 mg/kg/day and the median duration of therapy was 6 weeks. Age 5 was the smallest value defining two groups on which the correlation between dose and plasma levels had a different behaviour, and this relationship was especially significant for patients <5 years old (Spearman's rank correlation coefficient=0.38213, P=0.008). For patients <5 years old the median dose to achieve therapeutic levels was 38.0 mg/kg/day (12-40.0) and for those ≥5 years old it was 15 mg/kg (4-52). Voriconazole plasma levels showed a significant relationship with early outcome (P=0.0268), but not late outcome (P=0.2015). Overall mortality was 42% and a significant relationship with voriconazole therapeutic plasma levels was not demonstrated. A significant relationship was established between plasma levels above normal range and skin and neurological toxicity (P=0.0001), but this could not be demonstrated for liver toxicity. Our study confirms the large variability in voriconazole trough plasma levels in children and a trend to non-linear pharmacokinetics in older patients. In addition, doses significantly higher than those recommended in younger children seem warranted and a significant relationship between plasma voriconazole above the normal range and some adverse events is confirmed.

Oral Voriconazole Versus Intravenous Low Dose Amphotericin B for Primary Antifungal Prophylaxis in Pediatric Acute Leukemia Induction

Invasive fungal infections (IFI) are a major cause of infection-related mortality during induction chemotherapy of acute leukemia (AL) patients. Data on antifungal prophylaxis (AFP) in children are limited by retrospective design, small sample size, and variability of chemotherapy phases having different risk of IFI. There are no data comparing voriconazole versus amphotericin B (AmB) as AFP in either adult/pediatric AL. The objectives of this study were to compare efficacy and toxicity of AmB and voriconazole as AFP in pediatric AL patients. As a pilot study, total 100 children (≤15 y) with denovo acute myeloid leukemia and acute lymphoblastic leukemia were randomized to either oral voriconazole or low dose intravenous AmB as AFP during induction chemotherapy. Failure of prophylaxis occurred in 14/50 patients in voriconazole arm (1 proven mucormycosis, 1 possible IFI, 11 empirical antifungal therapy, and 1 withdrawal owing to hepatotoxicity) and 17/50 patients in AmB arm (3 possible IFI, 13 empirical antifungal therapy, and 1 withdrawal owing to difficult venous access) (P=0.66). Of the 29 patients who had failure of prophylaxis unrelated to drug toxicity, computed tomography of the chest showed infiltrates in 10 patients with 3/12 in voriconazole arm and 7/16 in AmB arm (P=0.43). Drug-related serious adverse events were 6% versus 30% in voriconazole and AmB arms, respectively (P<0.01). Further, total number of toxicities per patient in AmB arm were significantly higher as compared with voriconazole arm (P<0.0001). This is the first randomized study comparing voriconazole with AmB in pediatric AL patients as AFP during induction chemotherapy; our results showed that oral voriconazole seems to be comparable with AmB with less toxicity and more convenience. (ClinicalTrials.gov identifier: NCT00624143).

Rapid simultaneous determination of voriconazole and its N-oxide in human plasma using an isocratic high-performance liquid chromatography method and its clinical application

ObjectivesThe aim of this study was to develop a simultaneous determination method for voriconazole (VRCZ) and its N-oxide (VNO) in human plasma and to apply it to clinical samples. Design and methodsPlasma specimens were deproteinized with acetonitrile and then injected into an HPLC-UV system. VRCZ and VNO were separated on an ODS column filled with 2.3-μm particles using an isocratic mixture of acetonitrile/methanol/phosphate buffer 25/10/65 (v/v/v). Plasma concentrations of VRCZ and VNO in 25 patients were determined. ResultsBoth VRCZ and VNO were linear (r>0.999) over the concentration ranges of 0.1–8.0mg/L. The run time for quantification of the analytes was 4min. Interindividual variation in the plasma concentration of VRCZ that ranged from less than 0.1 to 6.96mg/L was observed. VNO concentrations weakly depended on VRCZ dosage. ConclusionsThe present method can contribute to the optimization of antifungal therapy using VRCZ.

INTRAVITREALLY IMPLANTABLE VORICONAZOLE DELIVERY SYSTEM FOR EXPERIMENTAL FUNGAL ENDOPHTHALMITIS

To investigate the therapeutic efficacy and optimal drug dose of an intravitreally implantable voriconazole (VCZ) drug delivery system (DDS) in experimental endophthalmitis of Aspergillus fumigatus. Vitrectomy was performed in albino rabbits with intravitreal inoculation of susceptible A. fumigatus. The animals were randomized into groups of control, polylactic-co-glycolic acid implantation, VCZ injection, and intravitreal VCZ DDS containing 0.5, 0.9, and 1.2 mg of VCZ, respectively. The therapeutic effect was assessed by clinical observation, histology, and microbiology. The inflammation in the VCZ injection and DDS groups was milder than the untreated and polylactic-co-glycolic acid groups (P ≤ 0.046). The 0.9-mg and 1.2-mg DDS groups presented milder anterior chamber and vitreous inflammation than the injection group during the first 3 weeks (P ≤ 0.044), but only the 1.2-mg DDS group had clearer vitreous thereafter (P ≤ 0.037). Smear and fungal culture showed negative results in all DDS groups. Normal histologic structure of the retina was observed in the eyes recovering from endophthalmitis. The therapeutic effect of intravitreal VCZ DDS on fungal endophthalmitis appears to be significantly better than intravitreal injection of VCZ. The optimal dose of VCZ in the DDS in this study was 1.2 mg.