Voriconazole Dose Research Articles

Pharmacokinetics of intravenous voriconazole in patients with liver dysfunction: A prospective study in the intensive care unit

ObjectivesTo characterize the pharmacokinetics (PK) of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction. MethodsPatients with liver dysfunction in the intensive care unit (ICU) were included prospectively. The Child–Pugh score was used to categorize the degree of liver dysfunction. The initial intravenous VRC dosing regimen comprised a loading dose of 300 mg every 12 h for the first 24 h, followed by 200 mg every 12 h. The first PK curves (PK curve 1) were drawn within one dosing interval of the first dose for 17 patients; the second PK curves (PK curve 2) were drawn within one dosing interval after a minimum of seven doses for 12 patients. PK parameters were estimated by non-compartmental analysis. ResultsThere were good correlations between the area under the curve (AUC0–12) of PK curve 2 and the corresponding trough concentration (C0) and peak concentration (Cmax) (r2 = 0.951 and 0.963, respectively; both p < 0.001). The median half-life (t1/2) and clearance (CL) of patients in Child–Pugh class A (n = 3), B (n = 5), and C (n = 4) of PK curve 2 were 24.4 h and 3.31 l/h, 29.1 h and 2.54 l/h, and 60.7 h and 2.04 l/h, respectively. In the different Child–Pugh classes, the CL (median) of PK curve 2 were all lower than those of PK curve 1. The apparent steady-state volume of distribution (Vss) of PK curve 1 was positively correlated with actual body weight (r2 = 0.450, p = 0.004). The median first C0 of 17 patients determined on day 5 was 5.27 (2.61) μg/ml, and 29.4% of C0 exceeded the upper limit of the therapeutic window (2–6 μg/ml). ConclusionsThe CL of VRC decreased with increasing severity of liver dysfunction according to the Child–Pugh classification, along with an increased t1/2, which resulted in high plasma exposure of VRC. Adjusted dosing regimens of intravenous VRC should be established based on Child–Pugh classes for these ICU patients, and plasma concentrations should be monitored closely to avoid serious adverse events.

Applying Pharmacogenomics to Antifungal Selection and Dosing: Are We There Yet?

This review summarizes recent literature for applying pharmacogenomics to antifungal selection and dosing, providing an approach to implementing antifungal pharmacogenomics in clinical practice. The Clinical Pharmacogenetics Implementation Consortium published guidelines on CYP2C19 and voriconazole, with recommendations to use alternative antifungals or adjust voriconazole dose with close therapeutic drug monitoring (TDM). Recent studies demonstrate an association between CYP2C19 phenotype and voriconazole levels, clinical outcomes, and adverse events. Additionally, CYP2C19-guided preemptive dose adjustment demonstrated benefit in two prospective studies for prophylaxis. Pharmacokinetic-pharmacodynamic modeling studies have generated proposed voriconazole treatment doses based on CYP2C19 phenotypes, with further validation studies needed. Sufficient evidence is available for implementing CYP2C19-guided voriconazole selection and dosing among select patients at risk for invasive fungal infections. The institution needs appropriate infrastructure for pharmacogenomic testing, integration of results in the clinical decision process, with TDM confirmation of goal trough achievement, to integrate antifungal pharmacogenomics into routine clinical care.

Variability of voriconazole concentrations in patients with hematopoietic stem cell transplantation and hematological malignancies: influence of loading dose, procalcitonin, and pregnane X receptor polymorphisms.

Voriconazole (VCZ) displays highly variable pharmacokinetics affecting treatment efficacy and safety. We aimed to identify the factors affecting VCZ steady-state trough concentration (Cssmin) to provide evidence for optimizing VCZ treatment regimens. A total of 510 Cssmin of 172 patients with hematopoietic stem cell transplantation and hematologic malignancies and their clinical characteristics and genotypes of FMO, POR, and PXR were included in this study. In univariate analysis, the standard loading dose of VCZ significantly increased the Cssmin of VCZ (P < 0.001). The Cssmin of VCZ was significantly correlated with patients' total bilirubin (TB) (P < 0.001) and procalcitonin (PCT) (P < 0.001). FMO3 rs2266780 (P = 0.025), POR rs10954732 (P = 0.015), PXR rs2461817 (P = 0.010), PXR rs7643645 (P = 0.003), PXR rs3732359 (P = 0.014), PXR rs3814057 (P = 0.005), and PXR rs6785049 (P = 0.013) have a significant effect on Cssmin of VCZ. Loading dose, TB, PCT level, and PXRrs3814057 polymorphism were independent influencing factors of VCZ Cssmin in the analysis of multivariate linear regression. And loading dose, PCT, and PXR rs3814057 had significant effects on the probability of the therapeutic window of VCZ. The high variability of VCZ Cssmin may be partially explained by loading dose, liver function, inflammation, and PXR polymorphisms. This study suggests the VCZ standard loading dose regimen significantly increased Cssmin and probability of the therapeutic window providing treatment benefits. Patients in the high PCT group may be more likely to exceed 5.5μg/mL, thus suffering from VCZ toxicity.

Invasive pseudomembranous upper airway and tracheal Aspergillosis refractory to systemic antifungal therapy and serial surgical debridement in an Immunocompetent patient

BackgroundThe development of respiratory infections secondary to Aspergillus spp. spores found ubiquitously in the ambient environment is uncommon in immunocompetent patients. Previous reports of invasive upper airway aspergillosis in immunocompetent patients have generally demonstrated the efficacy of treatment regimens utilizing antifungal agents in combination with periodic endoscopic debridement, with symptoms typically resolving within months of initiating therapy.Case presentationA 43-year-old previously healthy female presented with worsening respiratory symptoms after failing to respond to long-term antibiotic treatment of bacterial sinusitis. Biopsy of her nasopharynx and trachea revealed extensive fungal infiltration and Aspergillus fumigatus was isolated on tissue culture. Several months of oral voriconazole monotherapy failed to resolve her symptoms and she underwent mechanical debridement for symptom control. Following transient improvement, her symptoms subsequently returned and failed to fully resolve in spite of increased voriconazole dosing and multiple additional tissue debridements over the course of many years.ConclusionsInvasive upper airway aspergillosis is exceedingly uncommon in immunocompetent patients. In the rare instances that such infections do occur, combinatorial voriconazole and endoscopic debridement is typically an efficacious treatment approach. However, some patients may continue to experience refractory symptoms. In such cases, continued aggressive treatment may potentially slow disease progression even if complete disease resolution cannot be achieved.

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.

Impact of CYP2C19 Genotype and Drug Interactions on Voriconazole Plasma Concentrations: A Spain Pharmacogenetic-Pharmacokinetic Prospective Multicenter Study.

Voriconazole, a first-line agent for the treatment of invasive fungal infections, is mainly metabolized by cytochrome P450 (CYP) 2C19. A significant portion of patients fail to achieve therapeutic voriconazole trough concentrations, with a consequently increased risk of therapeutic failure. To show the association between subtherapeutic voriconazole concentrations and factors affecting voriconazole pharmacokinetics: CYP2C19 genotype and drug-drug interactions. Adults receiving voriconazole for antifungal treatment or prophylaxis were included in a multicenter prospective study conducted in Spain. The prevalence of subtherapeutic voriconazole troughs was analyzed in the rapid metabolizer and ultra-rapid metabolizer patients (RMs and UMs, respectively), and compared with the rest of the patients. The relationship between voriconazole concentration, CYP2C19 phenotype, adverse events (AEs), and drug-drug interactions was also assessed. In this study 78 patients were included with a wide variability in voriconazole plasma levels with only 44.8% of patients attaining trough concentrations within the therapeutic range of 1 and 5.5µg/ml. The allele frequency of *17 variant was found to be 29.5%. Compared with patients with other phenotypes, RMs and UMs had a lower voriconazole plasma concentration (RM/UM: 1.85±0.24µg/ml vs other phenotypes: 2.36±0.26µg/ml). Adverse events were more common in patients with higher voriconazole concentrations (p<0.05). No association between voriconazole trough concentration and other factors (age, weight, route of administration, and concomitant administration of enzyme inducer, enzyme inhibitor, glucocorticoids, or proton pump inhibitors) was found. These results suggest the potential clinical utility of using CYP2C19 genotype-guided voriconazole dosing to achieve concentrations in the therapeutic range in the early course of therapy. Larger studies are needed to confirm the impact of pharmacogenetics on voriconazole pharmacokinetics.

A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug-Drug Interactions.

Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail. In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim®. The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration-time curve (AUC), maximum concentration (Cmax), and trough concentrations for multiple dosings (Ctrough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time datasets over the full range of recommended intravenous and oral dosing regimens. The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregate Cmax ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregate Cmax ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1-2mg/L to < 5-6mg/L for Ctrough, while 400mg twice daily might be more suitable for rapid metabolizers (RMs; *1/*17, *17/*17) and normal metabolizers (NMs; *1/*1). When the model was integrated with independently developed CYP3A4 substrate models (midazolam and alfentanil), the observed AUC change of substrates by voriconazole was inside the 90% confidence interval of the predicted AUC change, indicating that CYP3A4 inhibition was appropriately incorporated into the voriconazole model. Both the in vitro assay and model-based simulations support TDI of CYP3A4 by voriconazole as a pivotal characteristic of this drug's PK. The PBPK model developed here could support individual dose adjustment of voriconazole according to genetic polymorphisms of CYP2C19, and DDI risk management. The applicability of modeling results for patients remains to be confirmed in future studies.

Pharmacokinetic/Pharmacodynamic Analysis of Voriconazole Against Candida spp. and Aspergillus spp. in Allogeneic Stem Cell Transplant Recipients.

To evaluate the adequacy of different dosing regimens of voriconazole for the prophylaxis of invasive candidiasis and aspergillosis in adult allogeneic stem cell transplant recipients by means of population pharmacokinetic (PK) modelling and simulation. Allogeneic stem cell transplant recipients receiving voriconazole were included in this observational study. A population PK model was developed. Three oral voriconazole-dosing regimens were simulated: 200, 300, and 400 mg twice daily. The pharmacodynamic target was defined as fAUC0-24/0.7. A probability of target attainment ≥90% was considered optimal. The cumulative fraction of response was defined as the fraction of patients achieving the pharmacodynamic target when a population of simulated patients is matched with a simulated population of different Candida spp. and Aspergillus spp. The percentage of patients with trough plasma concentrations at steady state (Ctrough) within the reference range (1-5.5 mg/L) was also calculated. A 2-compartment PK model was developed using data from 40 patients, which contributed 237 voriconazole plasma samples, including trough and maximum concentrations. Voriconazole 200, 300, and 400 mg twice daily achieved probability of target attainment ≥90% for minimal inhibitory concentration values ≤0.25, ≤0.38, and ≤0.50 mg/L, respectively. The cumulative fraction of response for A. niger, A. versicolor, and A. flavus increased >10% when increasing voriconazole dose from 200 to 400 mg twice daily (from 72.5% to 89.5% for A. niger; from 77.7% to 88.7% for A. versicolor; and from 82.4% to 94.9% for A flavus). The percentage of patients with Ctrough within the reference range increased 15% when voriconazole dose was increased from 200 to 300 mg twice daily. The PK simulations in this study suggest that transplant recipients on voriconazole prophylaxis against invasive candidiasis or aspergillosis are likely to achieve the target concentrations associated with the desired treatment outcomes if the maintenance dose is 200 mg twice daily. However, Aspergillus spp. with high minimal inhibitory concentrations could require higher maintenance doses.

1537. Multicenter Study with Therapeutic Drug Monitoring (TDM) of Voriconazole (VRCZ) in Japanese Patients

BackgroundTDM of VRCZ might be useful, especially in Asian people because of CYP2C19 genetic polymorphisms. However, limited data are available because of the small sample size.MethodsPatients who received VRCZ and had TDM were reviewed retrospectively at five institutions. Adequate VRCZ dosage was defined as a loading dose of 5–6 ± 0.5 mg/kg twice daily followed by a maintenance dose of 3–4 ± 0.5 mg/kg twice daily. For prophylaxis, the loading dose was left to the physician’s discretion. Optimal timing of TDM was defined as 4–7 days after starting therapy. Patients with adequate dosing and optimal timing of TDM were evaluated for analysis of trough levels (Cmin). Target Cmin was set at 1–5 µg/mL.ResultsThe study included 584 patients (treatment: 402; prophylaxis: 182). TDM was conducted on days 4–7 in 66.5% of patients (>7, 30.2%). A low adequate dosage (44.5%) was observed for treatment mainly because of a low performance of the loading dose (46.8%). Achievement of target Cmin was obtained in 62.7% (>5 µg/mL, 32.2%) in the treatment group and in 67.6% (11.0%) in the prophylaxis group. Seventy-one of 81 (81.7%) patients who required a dose reduction reached target Cmin by the second TDM. In 38 patients whose dose was not altered at oral switching, Cmin was significantly reduced from 2.5 ± 1.6 to 1.2 ± 1.3 μg/mL (P = 0.002), which indicated the necessity of TDM after oral switching. Hepatotoxicity occurred in 4.6% and visual symptoms in 7.9% of patients. Visual symptoms resolved without discontinuation of VRCZ in 73.9% of patients. Because of dosage adjustment based on TDM, high Cmin did not cause hepatotoxicity. However, the incidence of visual symptoms was significantly higher in patients with a high Cmin (12.7% vs. 5.4%, P = 0.002).ConclusionOne-third of Japanese patients who underwent VRCZ treatment with a loading dose showed high Cmin. Occurrence of hepatotoxicity was prevented with alteration of dosage in these patients (AMED, JP18fk0108045).Disclosures All authors: No reported disclosures.

Population Pharmacokinetics of Voriconazole and Optimization of Dosage Regimens Based on Monte Carlo Simulation in Patients With Liver Cirrhosis

Because voriconazole metabolism is highly influenced by liver function, the dose regimen of voriconazole should be carefully assessed in patients with liver cirrhosis. We aimed to identify significant factors associated with plasma concentrations. Blood samples were collected from patients with liver cirrhosis who received voriconazole, and voriconazole concentrations were determined. One-compartment model with first-order absorption and elimination appropriately characterized the in vivo process of voriconazole. The typical population value of voriconazole clearance (CL) was 1.45 L/h and the volume of distribution (V) was 132.12 L. The covariate analysis identified that CYP2C19 gene phenotype and Child-Pugh classification were strongly associated with CL and body weight had a significant influence on V. The results of the Monte Carlo simulation suggested that CYP2C19 gene phenotype was a critical factor for determining voriconazole dosage in patients with liver cirrhosis. The extensive metabolizer patients with Aspergillus fumigatus infections could be treated effectively with a recommended dose of 75 mg twice daily in mild to moderate liver cirrhosis and 100 mg once daily in moderate severe liver cirrhosis. However, the recommended dosage for Candida albicans infections patients was not achieved in present study.

Prediction models for voriconazole pharmacokinetics based on pharmacogenetics: AN exploratory study in a Spanish population

Individualisation of the therapeutic strategy for the oral antifungal agent voriconazole (VCZ) is extremely important for treatment optimisation. To date, regulatory agencies include CYP2C19 as the only major pharmacogenetic (PGx) biomarker in their dosing guidelines; however, the effect of other genes might be important for VCZ dosing prediction. We developed an exploratory PGx study to identify new biomarkers related to VCZ pharmacokinetics. We first designed a 'clinical practice VCZ-AUC prediction model' based on CYP2C19 to be used as a reference model in this study. We then designed a multifactorial polygenic prediction model and found that genetic variability in FMO3, NR1I2, POR, CYP2C9 and CYP3A4 partially contributes to VCZ total area under the concentration-time curve (AUC0-∞) interindividual variability, and its inclusion in VCZ AUC0-∞ prediction algorithms improves model precision. To our knowledge, there are no PGx studies specifically relating POR, FMO3 and NR1I2 polymorphisms to VCZ pharmacokinetic variability. Further research is needed in order to test the model proposed here.

Frequency of the CYP2C19*17 polymorphism in a Chilean population and its effect on voriconazole plasma concentration in immunocompromised children

Invasive fungal infections (IFIs) are the most frequent cause of morbidity and mortality in immunocompromised children. Voriconazole is the first-line antifungal choice in the treatment of IFIs like aspergillosis. Voriconazole pharmacokinetics vary widely among patients and voriconazole is metabolized mainly in the liver by the CYP2C19 enzyme, which is highly polymorphic. The CYP2C19*17 allele is characterized by the presence of four single nucleotide polymorphisms expressing an ultra-rapid enzyme phenotype with an accelerated voriconazole metabolism, is associated with low (sub-therapeutic) plasma levels in patients treated with the standard dose. Considering that in our center a high percentage of children have sub-therapeutic levels of voriconazole when treated with standard doses, we sought to determine the frequency of the CYP2C19*17 polymorphism (rs12248560) in a Chilean population and determine the association between voriconazole concentrations and the rs12248560 variant in immunocompromised children. First, we evaluated the frequency of the rs12248560 variant in a group of 232 healthy Chilean children, and we found that 180 children (77.6%) were non-carriers of the rs12248560 variant, 49 children (21.1%) were heterozygous carriers for rs12248560 variant and only 3 children (1.3%) were homozygous carriers for rs12248560 variant, obtaining an allelic frequency of 12% for variant in a Chilean population. To determine the association between voriconazole concentrations and the rs12248560 variant, we analyzed voriconazole plasma concentrations in a second group of 33 children treated with voriconazole. In these patients, carriers of the rs12248560 variant presented significantly lower voriconazole plasma concentrations than non-carriers (p = 0,011). In this study, we show the presence of the rs12248560 variant in a Chilean population and its accelerating effect on the pharmacokinetics of voriconazole in pediatric patients. From these data, it would be advisable to consider the variant of the patient prior to calculating the dosage of voriconazole.

Model-based Voriconazole Dose Optimization in Chinese Adult Patients With Hematologic Malignancies

PurposeThe objective of this study was to characterize the population pharmacokinetics of voriconazole and to identify factors that significantly affect pharmacokinetic parameters and to further investigate optimal dosage regimens in Chinese adult patients with hematologic malignancies. MethodsA prospective population pharmacokinetic analysis was performed on 186 concentration measurements obtained from 41 adult patients with hematologic malignancies. All enrolled patients were treated with voriconazole for diagnosed or suspected invasive fungal diseases. Oral voriconazole was routinely administered at a maintenance dose of 200 mg q12h. Serial blood samples were collected after steady-state of each patient. Monte Carlo simulation was applied to optimize dosage strategies. FindingsA one-compartment model with first-order absorption and elimination adequately described the data. The typical voriconazole clearance was 4.18 L/h, the volume of distribution was 88.9 L, and the absorption rate constant was 0.729 h−1. Clearance and steady-state exposure (AUC0–12) were found to be significantly associated with age and CYP2C19 phenotype. The average AUC0–12 of elderly patients (aged 60–90 years) was 2.1 times higher than that of relative younger patients (aged 18–59 years). The average AUC0–12 of poor metabolizers (PMs) was approximately 2.5 and 1.8 times higher than that of extensive and intermediate metabolizers (IMs), respectively. Considering both efficacy and tolerability, dosage regimens of 100 and 50 mg orally administered every 12 hours were recommended for elderly IMs and PMs, respectively. ImplicationsA population pharmacokinetic model for voriconazole in Chinese adult patients with hematologic malignancies was successfully developed and could well capture voriconazole's pharmacokinetic characteristics. Age and CYP2C19 phenotype were found to significantly influence voriconazole clearance and should be taken into consideration clinically for dose optimization. The optimal dosage strategies in specific clinical scenarios were proposed in this study based on model simulation. Because of the high incidence of mutant CYP2C19*2 and *3 alleles, genetic testing seems to be necessary for Asian elderly patients when voriconazole treatment is initiated.

Population Pharmacokinetics of Voriconazole in Chinese Patients with Hematopoietic Stem Cell Transplantation.

Voriconazole is widely recommended for the prevention and treatment of invasive fungal infections in hematopoietic stem cell transplantation patients. However, its use is limited by a narrow therapeutic range and large inter-individual variability. This study aimed to characterize the pharmacokinetics of voriconazole in Chinese hematopoietic stem cell transplantation patients, to explore factors affecting its pharmacokinetic parameters, and to provide recommendations for its optimal dosing regimens. A total of 121 serum concentration samples from 23 patients were retrospectively included. Voriconazole concentrations were detected, and patient clinical data were recorded. Population pharmacokinetic analysis was performed by a non-linear, mixed-effect modeling approach. Goodness-of-fit plots, bootstrap method, prediction-corrected visual predictive check and external validation by an independent group of seven patients were performed to evaluate the final model. A one-compartment model with first-order elimination successfully described the data. The absorption rate constant was fixed at 1.1h-1 and bioavailability was fixed at 0.895. The typical values for voriconazole clearance and distribution volume were 9.52 L/h and 155 L, respectively. CYP2C19*2 genotype and mycophenolate mofetil combination presented a significant impact on the clearance. Compared with CYP2C19*2 carriers, voriconazole clearance was proven to be higher in CYP2C19*1/*1 patients. A population pharmacokinetic model of voriconazole was successfully established in Chinese hematopoietic stem cell transplantation patients. Based on the final model, CYP2C19*2 genotyping coupled with therapeutic drug monitoring seems to be useful to guide voriconazole dosing and to explain subtherapeutic concentrations in clinical practice.

Impact of dose adaptations following voriconazole therapeutic drug monitoring in pediatric patients.

Voriconazole is the mainstay of treatment for invasive aspergillosis in immunocompromised pediatric patients. Although Therapeutic Drug Monitoring (TDM) of voriconazole is recommended, it remains unknown if TDM-based dose adaptations result in target attainment. Patients <19 years from two pediatric hematologic-oncology wards were retrospectively identified based on unexplained high voriconazole trough concentrations (Cmin >6mg/l). Patient demographics, clinical characteristics, treatment, voriconazole dosing information, voriconazole Cmin before and after adjustment based on TDM were obtained. Twenty-one patients, median (range) age 7.0 (1.2-18.5) years, were identified in two centers. First Cmin (3.1mg/l [0.1-13.5]) was obtained after 3 days (1-27) of treatment. The median of all Cmin (n = 485, median 11 per patient) was 2.16mg/l (0.0 (undetectable)-28.0), with 24.1% of Cmin < 1mg/l, 48.9% 1-4mg/l, 9.3% 4-6mg/l, and 17.7% >6mg/l. Intrapatient variability was large (94.1% for IV, 88.5% for PO). Dose increases at Cmin < 1mg/l resulted in an increased Cmin in 76.4%, with 60% between 1 and 4mg/l. Dose decreases at Cmin >6mg/l resulted in a decreased Cmin in 80%, with 51% between 1 and 4mg/l. Overall, in 45% of the cases (33 out of 55 and 12 out of 45) therapeutic targets were attained after dose adjustment. Fifty-five percent of initial Cmin was outside the therapeutic target of 1-4mg/l, with multiple dose adaptations required to achieve therapeutic concentrations. Only 60% and 51% of dose adaptations following sub- and supra-therapeutic Cmin, respectively, did result in target attainment. Intensive and continuous TDM of voriconazole is a prerequisite for ensuring adequate exposure in pediatric patients.

Dosing Antifungals in Obesity: a Literature Review

To summarize the available evidence regarding antifungal dosing in obese adults as well as to provide meaningful guidance on the dosing of each antifungal agent in obese patients. The pharmacokinetic evidence regarding dosing antifungal agents in obesity is limited. Fluconazole’s volume of distribution (VD) is influenced by BMI. Therapeutic drug monitoring (TDM) studies provide some insights into dosing voriconazole in obesity, but not with posaconazole. Isavuconazole seems to be unaffected by weight. The available data for echinocandins suggests that increased doses are likely necessary in obese patients. TDM may be beneficial, particularly for azoles when available in a timely manner. Fluconazole and voriconazole dosing should be based on total body weight and adjusted body weight, respectively. Posaconazole may have reduced exposures in obese patients, but data on its new dosage forms is lacking. Isavuconazole appears unaffected by weight. Echinocandin doses likely need to be increased in obese patients, but the exact weight and dosages remain elusive.

Correlation of CYP2C19 genotype with plasma voriconazole exposure in South-western Chinese Han patients with invasive fungal infections.

The aim of this study was to investigate the correlation between CYP2C19 genotype and dose-adjusted voriconazole (VCZ) trough concentrations (C0/dose).We analyzed the correlation between CYP2C192(681G>A), CYP2C193(636G>A), and CYP2C1917(-806C>T) genetic polymorphisms and the dose-corrected pre-dose concentration (C0/dose) in 106 South-western Chinese Han patients.The frequencies of variant alleles of CYP2C192, 3, and 17 were 29.7%, 4.25%, and 0.92%. For 49.3% of the VCZ samples, the therapeutic window between 1.5 and 5.5 μg/ml was reached. Following the first dose VCZ measurement, in subsequent samples the proportion of VCZ C0 within the therapeutic window increased, suggesting effective therapeutic drug monitoring (TDM) (P = .001). The VCZ C0 was significantly different (P = .010) between patients with normal metabolism (NMs), intermediate metabolism (IMs), and poor metabolism (PMs). The VZC C0/dose was 12.2 (interquartile range (IQR), 8.33-18.2 μg·ml/kg·day), and 7.68 (IQR, 4.07-16.3 μg·ml/kg·day) in PMs and IMs patients, respectively, which was significantly higher than in NMs phenotype patients (4.68; IQR, 2.51-8.87 μg·ml/kg·day, P = .008 and P = .014).This study demonstrated that the VCZ C0/dose was significantly influenced by the CYP2C19 genotype in South-western Chinese Han patients. In this patient population, more over-exposure was observed in patients with a CYP2C19 genotype associated with poor or intermediate metabolism. CYP2C19 genotype-based dosing combined with TDM will support individualization of VCZ dosing, and potentially will minimize toxicity and maximize therapeutic efficacy.

Voriconazole-induced QTc prolongation in a paediatric population.

To evaluate Corrected QT (QTc) interval prolongation (QTcP) in paediatric patients treated with voriconazole (VRC) and identify its associated risk factors in this setting. Clinical, VRC-related and QTc interval data were collected retrospectively from the electronic medical records of VRC-treated paediatric patients attending a large tertiary medical centre in 2011-2016 who underwent electrocardiography before and during therapy. Paired comparison of QTc intervals before and during VRC treatment was performed, adjusted for concurrent medications, electrolyte disturbances and co-morbidities. Fifty-five patients (mean age 10.1±5.4years) met the inclusion criteria; 34 had an oncologic or hemato-oncologic diagnosis. Mean QTc interval was 402.8±27.9msec before VRC treatment and 440.0±45.3msec on treatment (p<0.001). During treatment, 38 patients (61.8%) had QTcP ≥30msec and 17 (30.9%), QTcP ≥60msec; 10 patients (18.2%) had QTc ≥500msec of whom one acquired torsades de pointes. On multivariate analysis, older age (p=0.025), lower potassium level (p=0.025) and longer baseline QTc (0.032) were associated QTcP ≥60msec, but not daily or cumulative dose of VRC. This study demonstrated a high rate of clinically significant QTcP in VRC-treated children. Proper QTc monitoring, together with laboratory monitoring and electrolyte imbalance correction, is important to prevent cardiac arrhythmias in this patient population.

Mycotic keratitis caused by Scedosporium apiospermum in an immunocompetent patient

Abstract Clinical case A 51 year-old immunocompetent male was referred due to presenting with a large corneal ulcer with hypopyon in the right eye. Topical amphotericin B, fluconazole and moxifloxacin, as well as oral itraconazole were initially indicated. Following the report of mycotic structures on staining, topical natamycin was started. The result of the culture was reported two weeks later as, Scedosporium apiospermum (S. apiospermum), and topical voriconazole was then added. The response to treatment was very slow, and took five weeks after receiving triple therapy (natamycin, voriconazole and fluconazole) and one dose of intrastromal voriconazole, for the hypopyon to disappear. The final outcome was successful, achieving healing of the ulcer. The patient is waiting for a corneal transplant. Discussion A microbiological study is essential in patients in whom fungal keratitis is suspected. The treatment of choice against S. apiospermum is with voriconazole, but the combination of various antifungal agents may be required.

Interpersonal Factors in the Pharmacokinetics and Pharmacodynamics of Voriconazole: Are CYP2C19 Genotypes Enough for Us to Make a Clinical Decision?

Background: Invasive mycoses are serious infections with high mortality and increasing inci-dence. Voriconazole, an important drug to treat invasive mycosis, is metabolized mainly by the cytochrome P450 family 2 subfamily C member 19 enzyme (CYP2C19) and is affected by the genotypes of CYP2C19.Objective: We reviewed studies on how genotypes affect the pharmacokinetics and pharmacodynamics of voriconazole, and attempted to determine a method to decide on dosage adjustments based on genotypes, after which, the main characteristic of voriconazole was clarified in details. The pharmacokinetics of voriconazole are influenced by various inter and intrapersonal factors, and for certain populations, such as geriatric patients and pediatric patients, these influences must be considered. CYP2C19 genotype represents the main part of the interpersonal variability related to voriconazole blood concentrations. Thus monitoring the concentration of voriconazole is needed in clinical scenarios to minimize the negative influences of inter and intrapersonal factors. Several studies provided evidence on the stable trough concentration range from 1-2 to 4-6 mg/L, which was combined to consider the efficacy and toxicity. However, the therapeutic drug concentration needs to be narrowed down and evaluated by large-scale clinical trials.Conclusion: Though there is insufficient evidence on the relationship between CYP2C19 genotypes and clinical outcomes, there is a great potential for the initial voriconazole dose selection to be guided by the CYP2C19 genotype. Finally, voriconazole therapeutic drug monitoring is essential to provide patient-specific dosing recommendations, leading to more effective anti-fungal regimens to increase clinical effica-cy and reduce adverse drug reactions.