Voriconazole Serum Concentrations Research Articles

A Perspective Study on Therapeutic Drug Monitoring of Voriconazole in Pediatric Patients with Hematologic Disorders

Background: The incidence of invasive aspergillosis and the administration of voriconazole have risen among immunocompromised patients. Objectives: This study aimed to evaluate serum voriconazole concentration and its corresponding influential factors in pediatric patients with hematologic disorders. Methods: A total of 132 blood samples were collected from 44 pediatric patients with hematologic disorders infected with invasive aspergillosis and treated with voriconazole. Among these patients, 20.5% were classified as having proven invasive aspergillosis, 77.2% as probable, and 2.3% as possible. Voriconazole serum levels were evaluated using HPLC on the 3rd, 5th, and 7th days of treatment. Genotyping of the CYP2C19 alleles (*2, *3, and *17) was performed, and demographic and clinical data were gathered from records between 2018 to 2020. Results: The voriconazole concentration in 70.5% of patients and 77.3% of treatment cases (complete or partial) ranged from 1 to 5.5 µg/mL. Adverse events were observed in 4.5% of the patients. Genotyping of CYP2C19 genes revealed CYP2C1911 (5.4%), CYP2C19117 (16.2%), CYP2C1912 (51.4%), and CYP2C19217 (27%). Multivariate analysis using linear regression demonstrated that serum voriconazole concentration increased by 0.037 µg/mL per year of age and by 0.06 µg/mL for each unit increase in C-reactive protein (on the 3rd day of voriconazole therapy). Additionally, an increase in alanine aminotransferase level by 1 unit decreased the mean voriconazole concentration by 0.03 µg/mL. Of these patients, 65.9% were completely treated, 11.4% were partially treated, and 22.7% died. Conclusions: Serum voriconazole concentrations varied among pediatric hematologic patients receiving standard doses, with age, C-reactive protein, and alanine aminotransferase levels affecting the concentration of voriconazole in the sera of pediatric patients.

The Effect of Rifapentine and Rifampicin on Serum Voriconazole Levels Persist for 5 Days and 7 Days or More After Discontinuation in Tuberculosis Patients with Chronic Pulmonary Aspergillosis.

Voriconazole, a first-line therapeutic agent for chronic pulmonary aspergillosis, is metabolized by the cytochrome 450 enzymes, specifically CYP2C19 and CYP3A4. Rifampicin and rifapentine act as inducers of the cytochrome P450 enzyme. The current study explored the potential drug interactions arising from the co-administration of voriconazole with either rifampicin or rifapentine, as well as the duration of this effect on serum voriconazole levels after discontinuation of rifampicin or rifapentine. A retrospective study was conducted in tuberculosis patients with chronic pulmonary aspergillosis. These patients underwent a combination therapy involving voriconazole and rifampicin or rifapentine, or they were treated with voriconazole after discontinuation of rifampicin or rifapentine. The serum concentrations of voriconazole at steady-state were monitored. Data on demographic characteristics and the serum voriconazole levels were used for statistical analyses. A total of 124 serum voriconazole concentrations from 109 patients were included in the study. The average serum concentration of voriconazole fell below the effective therapeutic range in patients treated with both voriconazole and rifampicin or rifapentine. Notably the co-administration of rifapentine led to a substantial (>70%) decrease in serum voriconazole levels in two patients. Moreover, this interfering effect persisted for at least 7 days following rifampicin discontinuation, while it endured for 5 days or more after discontinuation of rifapentine. Concomitant use of voriconazole and rifampicin or rifapentine should be avoided, and it is not recommended to initiate voriconazole therapy within 5 or 7 days after discontinuation of rifapentine or rifampicin. Therapeutic drug monitoring not only provides a basis for the adjustment of clinical dose, but also serves as a valuable tool for identifying drug interactions.

Pharmacogenetic implementation for CYP2C19 and pharmacokinetics of voriconazole in children with malignancy or inborn errors of immunity

BackgroundVoriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity. MethodsCYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination. ResultsVoriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of Vmax inhibition [Vmax, inh] = 100 %; Vmax = 0). The estimated parameters of Vmax,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher. ConclusionCYP2C19 genetic polymorphisms, γ-GTP, and CRP affect Vmax,inh of voriconazole in children with malignancy or inborn errors of immunity.

WHICH TOOL IS THE BEST GUIDE OPTIMIZE THE VORICONAZOLE DOSAGE: THERAPEUTIC DRUG MONITORING OR CYTOCHROME P450 POLYMORPHISM?

Voriconazole (VCZ) is the drug of choice for invasive aspergillosis (IA). However, narraow therapeutic range and variable pharmacokinetics can effect the success of the therapy. VCZ serum concentration is influenced by several factor including CYP450 polymorphisms primarily by CY2C19. Therapeutic drug monitoring (TDM) of VCZ is highly recommended to check adequate serum concentrations. Herein, we investigated the usefulness of detecting CYP450 polymorphism. Patients with hematological malignancies were included in the study.CYP450 polymorphisms which are responsible for metabolism of VCZ were investigated using RT-PCR. TDM of VCZ was peformed usingLC/MS/MS.11 patients were included in the study. Frequencies of CYP2C19 genotypes are 27% for intermediate metabolizer; 36% rapid metabolizer, 18% for ultra rapid metabolizer, 18% for normal metabolizer. Two patients experienced dose related side effects and one of these patient’s voriconazole blood concentration was supratherapeuticAlthough VCZ is the drug of choice for thetreatment of IA, the variabality of the pharmacokinetics can influence the success of therapy significantly. Therefore implementing the pharmacogenetic testing and therapeutic drug monitoring to clinical practice might help clinicians to provide improved care to patients and improve treatment outcomes.

Population pharmacokinetics and covariate-based dosing individualization of voriconazole in lung transplant recipients

This study aimed to explore pharmacokinetics of voriconazole and its covariates in lung transplant recipients using population approach in order to propose dosing individualization. Data from routine therapeutic drug monitoring in adult lung transplant recipients treated with oral voriconazole were analysed with a three-stage population pharmacokinetic model using nonlinear mixed-effects modelling. Monte Carlo simulations based on final voriconazole pharmacokinetic model were used to generate the theoretical distribution of pharmacokinetic profiles at various dosing regimens. A total of 78 voriconazole serum concentrations collected from 40 patients were included in pharmacokinetic analysis. The only significant covariate was age for voriconazole clearance. Population voriconazole apparent clearance started at 32.26 L/h and decreased by 0.021 L/h with each year of patient’s age, while population apparent volume of distribution was 964.46 L. Based on this model, we have proposed an easy-to-use dosing regimen consisting of a loading dose of 400 mg every 12 h for the first 48 h of treatment followed by maintenance dose of 300 mg every 12 h in patients aged up to 59 years, or by maintenance dose of 200 mg every 12 h in patients aged above 59 years.

Higher Weight-Based Doses Are Required to Achieve and Maintain Therapeutic Voriconazole Serum Trough Concentrations in Children.

Children require weight-based voriconazole doses proportionately larger than adults to achieve therapeutic serum trough concentrations (1-6 mcg/mL). The objective of this quality improvement project was to determine the initial dose, proportion of patients achieving target concentrations with initial dosing, and subsequent therapeutic drug monitoring and dose modifications needed to achieve and maintain therapeutic voriconazole concentrations in children. This retrospective study evaluated children aged <18 years treated with voriconazole during the study period. Dosing and therapeutic drug monitoring (TDM) values were collected and compared by age. Data are presented as median (IQR), unless otherwise stated. Fifty-nine patients, aged 10.4 (3.7-14.7) years and 49% female, met inclusion criteria; 42 had at least 1 steady-state voriconazole serum trough concentration measured. Twenty-one of 42 (50%) achieved the target concentration at the first steady-state measurement. An additional 13 of 42 (31%) achieved the target following 2 to 4 dose modifications. The dose required to first achieve a value in the target range was 22.3 (18.0-27.1) mg/kg/day in children aged <12 years and 12.0 (9.8-14.0) mg/kg/day in children aged ≥12 years. After reaching the target, 59% and 81% of repeated steady-state measurements were in the therapeutic range in patients aged <12 years and ≥12 years, respectively. Reaching therapeutic voriconazole serum trough concentrations required doses larger than currently recommended by the American Academy of Pediatrics. Multiple dose adjustments and TDM measurements were required to achieve and maintain therapeutic voriconazole serum concentrations.

Voriconazole exposure is influenced by inflammation: A population pharmacokinetic model.

Voriconazole is an antifungal drug used for the treatment of invasive fungal infections. Due to highly variable drug exposure, therapeutic drug monitoring (TDM) has been recommended. TDM may be helpful to predict exposure accurately, but covariates, such as severe inflammation, that influence the metabolism of voriconazole have not been included in the population pharmacokinetic (popPK) models suitable for routine TDM. To investigate whether the effect of inflammation, reflected by C-reactive protein (CRP), could improve a popPK model that can be applied in clinical care. Data from two previous studies were included in the popPK modelling. PopPK modelling was performed using Edsim++. Different popPK models were compared using Akaike Information Criterion and goodness-of-fit plots. In total, 1060 voriconazole serum concentrations from 54 patients were included in this study. The final model was a one-compartment model with non-linear elimination. Only CRP was a significant covariate, and was included in the final model and found to affect the maximum rate of enzyme activity (Vmax). For the final popPK model, the mean volume of distribution was 145 L [coefficient of variation percentage (CV%)=61%], mean Michaelis-Menten constant was 5.7 mg/L (CV%=119%), mean Vmax was 86.4 mg/h (CV%=99%) and mean bioavailability was 0.83 (CV%=143%). Internal validation using bootstrapping resulted in median values close to the population parameter estimates. This one-compartment model with non-linear elimination and CRP as a covariate described the pharmacokinetics of voriconazole adequately.

Influence of switching from intravenous to oral administration on serum voriconazole concentration.

While bioavailability of oral voriconazole is known to be >90%, several reports have observed much lower oral bioavailability. The aim of the present study was to assess the oral bioavailability of voriconazole in clinical use by evaluating the change in serum voriconazole concentration in patients who received intravenous-to-oral switch therapy with the same dose of voriconazole. A single-centre, retrospective cohort study was conducted at the 614-bed Gifu University Hospital in Japan. Patients who received intravenous-to-oral switch therapy with the same dose of voriconazole between 1 January 2011 and 31 December 2018 were enrolled in the present study. We evaluated changes in serum voriconazole concentration before and after switch therapy. Voriconazole trough concentrations significantly decreased following oral compared to intravenous treatment (2.5±1.5µg/mL vs 3.3±2.0µg/mL, p=0.021). The median change rate of serum concentration by switching the route of administration was 82.7%, with wide inter-individual variability (range 27.2-333.3%). Further, concomitant glucocorticoid administration was a significant protective factor for reducing serum concentration (OR 0.16, 95% CI 0.03-0.79, p=0.025). Switching from intravenous to oral treatment resulted in a significant decline in voriconazole trough concentrations with wide inter-individual variability. Therefore, measurement of serum concentration for dose adjustment should be performed after switching to the oral form.

Factors Associated With Voriconazole Concentration in Pediatric Patients.

Serum concentrations of voriconazole are difficult to predict, especially in pediatric patients, because of its complex pharmacokinetic characteristics. This study aimed to identify the factors associated with the concentration of voriconazole in pediatric patients. This cohort study was based on retrospective data collection and involved the administration of voriconazole to pediatric patients younger than 18 years, between January 2010 and August 2017. Electronic medical records of the patients were reviewed to collect demographic characteristics, voriconazole treatment regimen, and factors that could potentially influence voriconazole trough concentrations. A voriconazole trough serum concentration of less than 1.0 mcg/mL or greater than 5.5 mcg/mL was defined as outside the therapeutic range and was set as the outcome of this study. Among the 114 patients enrolled, 61 patients were included in the analysis. Oral administration of a maintenance dose of voriconazole and C-reactive protein (CRP) level were significantly and independently associated with a low initial trough concentration of voriconazole (<1.0 mcg/mL). Alanine aminotransferase levels were a significant factor associated with a high initial trough concentration of voriconazole (>5.5 mcg/mL) after adjusting for sex, age, weight, and serum creatinine (odds ratio 5.42; 95% confidence interval 1.34-21.97). Considering the variability of voriconazole concentrations in pediatric patients, monitoring certain parameters and considering the route of administration could help determine the therapeutic range of voriconazole and subsequently avoid unwanted effects.

Genetic polymorphisms of transient receptor potential melastatin 1 correlate with voriconazole-related visual adverse events.

Causes of voriconazole-related visual adverse events (VVAE) remained controversial. We aimed to explore the relationship between voriconazole serum concentrations and VVAE as well as the potential influence of transient receptor potential melastatin 1 (TRPM1) on VVAE. This prospective observational cohort study was done in two stages. Patients who received voriconazole for invasive fungal diseases were consecutively enrolled. Correlations between voriconazole trough levels and VVAE were explored in 76 patients. Genotyping was further conducted for 17 tag SNPs of TRPM1 in a larger population of 137 patients. Genotype distributions were compared between patients with and without VVAE. Of the 76 patients, a total of 229 steady-state voriconazole trough levels were evaluated, 69.9% of which were within the target range (1-5.5mg/L). No correlations were found between voriconazole trough levels and VVAE. Of the total 137 patients, VVAE occurred in 37 (27.0%) patients, including visual hallucination (13.9%, 19/137) and visual disturbances (19.0%, 26/137). Significant difference in TRPM1 genotype distribution was only observed in patients with visual hallucination but not with visual disturbances. We found that rs890160 G/T genotype was under-presented (OR, 0.11; 95% CI, 0.01-0.84; P=.011) and rs1378847 C/C genotype was more frequently detected (OR, 8.89; 95% CI, 1.14-69.02; P=.013) in patients with visual hallucination when compared with those without. Transient receptor potential melastatin 1 was genetically associated with voriconazole-related visual hallucination. The correlation was failed to found between voriconazole trough levels and VVAE.

Oral administration of voriconazole with surgical fungal plaque debridement for the treatment of sinonasal aspergillosis with cribriform plate lysis in three dogs.

3 dogs with chronic sinonasal signs (sneezing, nasal discharge, or epistaxis [or a combination of signs]) were examined. For all 3 dogs, CT revealed variable degrees of nasal turbinate destruction and frontal sinus involvement with cribriform plate lysis. Fungal plaques were detected during rhinoscopy or sinusoscopy. Results of fungal culture (2 dogs) or cytologic examination of a plaque specimen (1 dog) supported a diagnosis of sinonasal aspergillosis. All dogs underwent surgical rhinotomy or sinusotomy (or both) for fungal plaque debridement followed by oral treatment with voriconazole and periodic physical examinations, clinicopathologic analyses, and assessments of serum drug concentrations for a period ≥ 22 weeks. All dogs had considerable to complete reduction of their clinical signs and tolerated voriconazole treatment with minimal adverse effects. Adverse effects included development of reversible neurotoxicosis (associated with high serum voriconazole concentration) and mildly high serum liver enzyme activities. The dosage of voriconazole administered to achieve therapeutic serum concentrations (2.5 to 3.3 mg/kg [1.1 to 1.5 mg/lb], PO, q 12 h) was substantially lower than dosages suggested by previously published studies in dogs. The 3 dogs remained clinically normal or had mild clinical signs after voriconazole discontinuation for follow-up times of 6 to 15 months. Findings in these 3 dogs indicated that surgical fungal plaque debridement followed by oral treatment with voriconazole may be an effective treatment option for dogs with sinonasal aspergillosis and cribriform plate lysis. Further evaluation of this treatment regimen with repeated CT examinations and longer follow-up times is warranted.

Therapeutic drug monitoring and safety of voriconazole in elderly patients

BackgroundData on therapeutic drug monitoring of voriconazole in elderly patients are limited. Impaired liver function and an inflammatory state in elderly individuals are hypothesized to impact the voriconazole serum level. MethodsA total of 166 adult patients (317 trough concentrations) who underwent voriconazole therapeutic drug monitoring were enrolled. The voriconazole trough concentration, its associated covariates, and its correlation with adverse effects in 73 elderly (≥60 years) patients (116 trough concentrations) were analyzed and compared to those in 93 adult (<60 years) patients. ResultsThe voriconazole trough concentration was 4.31 ± 3.03 μg/mL (range, 0.4–15.5 μg/mL) in the elderly patients, which was significantly higher than the 3.11 ± 2.13 μg/mL (range, 0.4–14.3 μg/mL) in the adult patients (P = 0.001). The proportion of voriconazole trough concentrations higher than 5 μg/mL was 35.3% in the elderly patients, which was also significantly higher than the 15.4% in the adult patients (P < 0.001). A stepwise multivariable linear regression model showed that procalcitonin and gamma-glutamyl transpeptidase were independently associated factors in the elderly patients (OR = 2.590, 95% confidence interval [CI] = 1.506–3.673, P = 0.001; OR = −0.016, 95% CI = −0.027 to −0.006, P = 0.005). Receiver operating characteristic (ROC) curve analysis indicated that procalcitonin concentrations of ≥1.31 ng/mL increased the incidence of a voriconazole trough concentration higher than 5 μg/mL (95% CI = 0.53–0.87 μg/mL) (P = 0.03). The incidence of decreased albumin concentrations was higher in the elderly cohort than that in the adult cohort independent of the voriconazole trough concentration (P < 0.05). ConclusionsThe voriconazole trough concentrations in the elderly patients were significantly higher than those in the adult patients who received voriconazole therapy and were significantly affected by severe inflammation as evaluated by the procalcitonin concentration. Frequent monitoring of the voriconazole serum concentration and procalcitonin concentration during and after severe inflammation is critical to maintain the voriconazole serum concentration within the therapeutic range.

2112. Voriconazole for Primary Prophylaxis: A Decade of Trends and Outcomes

BackgroundInvasive fungal infections (IFI) continue to affect the immunocompromised patient population. Many of these patients require antifungal prophylaxis. Voriconazole is an azole antifungal that has been utilized for preventing IFIs but does not have an approved indication for prophylaxis.MethodsAdult patients admitted to Duke University Hospital from January 1, 2005 to December 31, 2015 who had received at least 2 days of systemic voriconazole as primary prophylaxis were included in this retrospective medical records review. Demographics, underlying comorbidities, adverse events, drug interactions, voriconazole blood concentrations, and microbiological data were assessed.ResultsOur review identified 403 patients receiving voriconazole for primary prophylaxis. 220 (55.6%) were male, 303 (75.2%) were Caucasian, and the mean age was 46.0 ± 15.7 years. 233 (57.8%) had leukemia, and 63 (15.6%) had lymphoma. 301 (74.7%) underwent hematopoietic transplant (BMT), and 45 (11.2%) had a solid-organ transplant. 176 (43.7%) patients received chemotherapy and 261 (64.8%) received immunosuppressive drugs. The mean voriconazole total daily maintenance dose was 416.1 ± 65.9 mg (5.5 ± 1.6 mg/kg/day). Patients received inpatient voriconazole for a mean of 19.5 ± 16.5 days. 371 (92.1%) patients received a concomitant interacting drug. Only 140 (43.7%) patients had therapeutic drug monitoring. The mean first voriconazole serum concentration was 1.8 ± 1.7 mg/L. 87 (21.6%) patients discontinued voriconazole prematurely; 41 (10.2% overall) of these patients had an adverse event requiring discontinuation. 5 had breakthrough fungal infections with microbiological data identifying a fungal species, which included Rhizopus spp. among others.ConclusionVoriconazole is frequently used for primary prophylaxis of IFIs and most commonly in BMT. It appears to be relatively well tolerated with some adverse side-effects (~10%) despite many potential drug–drug interactions and provides appropriate fungal coverage for many immunosuppressed patients. However, few patients had breakthrough fungal infections while receiving voriconazole. In a real-world setting, voriconazole can provide antifungal prevention in certain high-risk patients.Disclosures All authors: No reported disclosures.

Voriconazole trough concentration and hepatotoxicity in patients with low serum albumin .

We aimed to investigate the relationship between voriconazole (VRCZ) trough concentrations and hepatotoxicity and to evaluate whether the recommended trough concentration is adequate in our clinical setting. A retrospective study was performed to investigate the relationship between serum VRCZ concentrations and the development of hepatotoxicity at the Kindai University Nara Hospital. Patients treated with VRCZ from March 2010 to January 2018 were identified from the medical records. A total of 42 patients (mean age of 61.9 ± 16.9 years; 33 males and 9 females) were enrolled in this study. Hepatotoxicity developed in 28.6% (12/42) of patients treated with VRCZ, and 91.7% (11/12) of these patients developed hepatotoxicity within 3 weeks after initiating the treatment. Significantly increased aspartate aminotransferase (AST; p < 0.001), alkaline phosphatase (ALP; p < 0.001), and alanine aminotransferase (p = 0.001) levels were observed after the initiation of VRCZ therapy. In addition, significant positive correlations between AST and VRCZ trough concentrations (p = 0.017) and between ALP and VRCZ trough concentrations (p = 0.012) were observed. VRCZ trough concentration was identified as a significant independent risk factor for hepatotoxicity (adjusted odds ratio: 1.611, 95% confidence interval: 1.131 - 2.579, p = 0.006), and the cutoff serum trough concentration was calculated to be 4.2 μg/mL. VRCZ-induced hepatotoxicity should be noted in the early stages of therapy. A sustained VRCZ trough concentration of ~ < 4.2 μg/mL is recommended to prevent hepatotoxicity in patients with low serum albumin levels.

Voriconazole concentration is inversely correlated with corticosteroid usage in immunocompromised patients.

Voriconazole (VRCZ) is a broad-spectrum antifungal agent that can be administered both orally and intravenously. A high level of intra- and interindividual variability in serum drug therapeutic concentrations has been reported. We analyzed the influence of corticosteroid use on serum VRCZ concentration by assessing the correlation between corticosteroid dose and VRCZ trough level. Immunocompromised patients treated with VRCZ with or without corticosteroid use from June 2010 to March 2017 (6years and 8months) were reviewed in our institute. VRCZ and the corticosteroids were administered orally or intravenously. Corticosteroid treatment was considered as "concurrent" only if it was administered within 3days before or after the initiation of VRCZ. All corticosteroids were converted to a prednisolone-based dosage according to their anti-inflammatory effect (relative glucocorticoid activity). VRCZ concentration was measured at the trough point on the day of steady state. A total of 85 samples were obtained from 38 patients. The medical records of 23 women and 15 men, with a median age of 61years (range: 35-86), were reviewed. Twenty-one patients (55.3%, 21/38) received chemotherapy, and 28 (73.7%, 28/38) received corticosteroid therapy. The average and median daily doses of corticosteroids were 59.2 and 89.8mg, respectively (range: 0.714-377). VRCZ concentration was inversely correlated with corticosteroid dose (r=-.26). The VRCZ concentration was significantly decreased in the corticosteroid user compared to nonuser (P=.013). We evaluated the association of VRCZ concentration and corticosteroid dose in 3 patients among our cohorts for whom more than 5 points of data were available. Intraindividual analysis revealed the trough level of VRCZ concentration decreased as the corticosteroid dose increased. The patients' underlying diseases were hematological diseases (n=25) and immunological diseases (n=13). Among accrual patients, no patients were undergoing stem cell transplantation, and no patients were treated with known confounders such as calcineurin inhibitors or phenytoin. VRCZ might be metabolized by an enzyme induced by corticosteroid treatment; therefore, intraindividual variation in VRCZ metabolism should be considered prior to concurrent treatment, especially for patients with hematological malignancies treated with corticosteroids.

PP-46 Voriconazole dosing strategies in young children: challenges and recommendations

Background Voriconazole pharmacokinetics (PK) have been studied in paediatric studies and described by popu-lation pharmacokinetic modelling.1 Using the currently approved intravenous (IV) dosing regimen,2 ,3 paediatric patients provided 30 trough samples resulting in a ob-served median (range) of 1.2 (0.11–17.4) mg/L.1 This illustrates the highly variable pharmacokinetic (PK) pro-file of voriconazole in children. The aim of this case series is to evaluate the effectiveness of dosing guidelines in combination with routine therapeutic drug monitoring (TDM) to achieve therapeutic serum concentrations of voriconazole in young cancer patients (age 0–6 years old). Methods At the VUmc, paediatric patients are treated using TDM. Voriconazole plasma concentrations are monitored and dosing regimens are individualised, aiming at trough levels of 1–6 mg/L depending on the location of the Asper-gillus. A case series of 4 children (age 0–6 years) is presented. Results Highly variable voriconazole exposure (n=4) were observed. Case 1 Boy, 13 months, acute myeloid leukaemia: Loading dose 9 mg/kg tid (IV), maintenance 8 mg/kg tid (IV) [2] resulted in supratherapeutic levels, hepatic toxicity and circulatory insufficiency. Root cause: CYP2C inhibition by previous prophylactic Itraconazole treatment. Itraconazole has a half-life time up to two days. Therapeutic voriconazole levels achieved at 6 mg/kg tid (IV); Case 2 Boy, 5 years, acute lymphatic leukaemia: Doses varying between 7 mg/kg tid IV and 11 mg/kg tid IV during 4 months of IV therapy. Highly variable trough concentrations varying from 0.10–13.3 mg/L; 65% within the target range of 2–6 mg/L for cerebral Aspergillus: Case 3 Girl, 7 months, mixed phenotype acute leukaemia: Load-ing dose 6 mg/kgbid (IV), maintenance 9 mg/kgbid (PO) resulted in subtherapeutic trough levels (0.1–0.2 mg/L), possibly due to high first pass metabolism. Case 4 Girl, 5 years, acute lymphatic leukaemia: Loading dose 10 mg/kgbid (PO), high maintenance dose of 23 mg/kgbid (PO) re-sulted in therapeutic levels. Higher doses of 30 mg/kgbid resulted in a more than dose-proportional increase of ex-posure (trough level 22 mg/L), suggesting non-linear PK. Conclusion Voriconazole PK is highly variable in pedi-atric cancer patients, which can only partly be attributed to drug interactions and co-morbidities. A starting dose of 18 mg/kg (IV) is recommended and could be adminis-tered as 6 mg/kg tid (IV).2 Intensive TDM (at least twice weekly) and daily in-depth status reviews are recom-mended to achieve therapeutic drug levels.

Performance evaluation of enzyme immunoassay for voriconazole therapeutic drug monitoring with automated clinical chemistry analyzers

ObjectiveVoriconazole is a triazole antifungal developed for the treatment of fungal infectious disease, and the clinical utility of its therapeutic drug monitoring has been evaluated. Recently, a new assay for analyzing the serum voriconazole concentration with an automated clinical chemistry analyzer was developed. We evaluated the performance of the new assay based on standardized protocols. MethodsThe analytical performance of the assay was evaluated according to its precision, trueness by recovery, limit of quantitation, linearity, and correlation with results from liquid chromatography-tandem mass spectrometry (LC-MS/MS). The evaluation was performed with the same protocol on two different routine chemistry analyzers. All evaluations were performed according to CLSI Guidelines EP15, EP17, EP6, and EP9 [1–4]. ResultsCoefficients of variation for within-run and between-day imprecision were 3.2–5.1% and 1.5–3.0%, respectively, on the two different analyzers for pooled serum samples. The recovery rates were in the range of 95.4–102.2%. The limit of blank was 0.0049μg/mL, and the limit of detection of the samples was 0.0266–0.0376μg/mL. The percent recovery at three LoQ levels were 67.9–74.6% for 0.50μg/mL, 75.5–80.2% for 0.60μg/mL, and 89.9–96.6% for 0.70μg/mL. A linear relationship was demonstrated between 0.5μg/mL and 16.0μg/mL (R2=0.9995–0.9998). The assay correlated well with LC-MS/MS results (R2=0.9739–0.9828). ConclusionsThe assay showed acceptable precision, trueness, linearity, and limit of quantification, and correlated well with LC-MS/MS. Therefore, its analytical performance is satisfactory for monitoring the drug concentration of voriconazole.

Therapeutic Drug Monitoring of Voriconazole: Comparison of Bioassay with High-Performance Liquid Chromatography

Background: Voriconazole is a triazole antifungal agent with considerable inter and intra-individual variability in plasma concentrations. Therapeutic drug monitoring of voriconazole plays an important role in optimizing the efficacy and safety of the drug in patients. Objectives: This study aimed at evaluating the performance of a simple agar well diffusion bioassay and comparing its utility with high-performance liquid chromatography (HPLC). Methods: The clinical isolate of voriconazole hyper susceptible Candida kefyr was used for a simple agar well diffusion bioassay method. Acetonitrile precipitations followed by reverse-phase HPLC on C18 column, with ultra violet detection, were used for HPLC. Cross validation was done by evaluating the accuracy and precision of both methods in a large cohort of 180 samples from 60 voriconazole-treated patients. Results: The validated bioassay method and HPLC, as a reference method, were found to be accurate and precise. A good correlation was found between the 2 methods with similar analytical range (0.25 – 16 µg/mL). The result of linear regression analysis revealed bioassay = 0.961 (HPLC) +0.148; R2 = 0.965; correlation coefficient = 0.982; n = 180. Voriconazole serum concentration of patients ranged from 0.25 µg/mL to 5.41 µg/mL when using HPLC, and from 0.25 µg/mL to 5.71 µg/mL when using the bioassay method. Conclusions: When laboratories are not equipped with HPLC, bioassay may be a reliable technique with sufficient accuracy and precision for monitoring voriconazole plasma concentration.

Impact of CYP2C19 polymorphisms on serum concentration of voriconazole in iranian hematological patients

Objective:This study aimed to determine the portion of Iranian patients who attain therapeutic serum concentrations of voriconazole (VRCZ) following administration of fixed doses. In addition, the effect of CYP2C19 polymorphism on serum levels of VRCZ was also investigated.Methods:Forty-eight adult patients of Iranian origin with hematologic malignancies, who received VRCZ for treatment of invasive aspergillosis, were recruited into the study. Blood samples were drawn at day 4 of treatment to measure trough drug concentrations and determine genotyping of CYP2C19 polymorphisms of each patient. High-performance liquid chromatography method was used for measuring VRCZ serum level and CYP2C19 polymorphisms were conducted by Sanger sequencing. Demographic and clinical characteristics of patients alongside with CYP2C19 polymorphisms were assessed to determine the effective factor/s on VRCZ serum concentration.Findings:Seventy-three percent of patients achieved therapeutic serum concentrations of VRCZ with administration of usual fixed doses in clinical practice. There was no correlation between weight-adjusted dose and serum concentrations of VRCZ. Mean serum levels were significantly different neither in genders nor in routes of administrations. Extensive and ultrarapid metabolizers (URMs) comprised 48.7% and 21.6% study population, respectively. CYP2C19 polymorphism dramatically influenced the trough levels of VRCZ, so that all patients with subtherapeutic levels expressed URM phenotype.Conclusion:With respect to high incidence of URM phenotype in Iranian population, and observed association of this phenotype with sub-therapeutic levels in our study, performing therapeutic drug monitoring is strongly recommended for all patients.

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.