Voriconazole Trough Concentrations Research Articles

Voriconazole monitoring in children with invasive fungal infections.

The primary objective of this study was to determine the optimal daily dose of voriconazole required to achieve therapeutic trough concentrations in children 1 month to 18 years of age. The secondary objective was to analyze the association between voriconazole trough concentrations and clinical and microbiological outcomes, toxicity, and mortality. This study was a retrospective chart review (October 2009 to August 2012) of pediatric oncology/bone marrow transplant patients with proven or probable invasive fungal infections treated with intravenous or oral voriconazole. Patients were excluded if they were older than 18 years of age, had no voriconazole concentrations drawn during the study period, or received voriconazole prior to the study period. Thirty-four patients were reviewed; 11 patients met all criteria for inclusion. There were 6 males and 5 females, with a median age of 8 years (range: 0.8-14.8) and a median weight of 27 kg (range: 9-74). Doses were adjusted to a median 6 mg/kg/dose (range: 3-8.7 mg/kg/dose) given every 8 (n = 5) to 12 (n = 6) hours; dose regimens varied greatly. All but 1 child achieved a voriconazole trough concentration above 1 mg/L; 7 children had a trough concentration above 2 mg/L. The median time to achieve a therapeutic trough concentration was 11 days (range: 6-37 days). Therapy failed for 4 of 11 patients, including 3 of the 4 youngest patients (p=0.022). Three of the 4 for whom therapy failed also had voriconazole trough concentrations less than 2 mg/L; this did not reach statistical significance. Voriconazole therapy was discontinued in 2 patients due to toxicity. This study confirmed that voriconazole pharmacokinetics vary greatly in pediatric oncology/bone marrow transplant patients. "Optimal" doses varied over nearly a 3-fold range. Younger patients may be at greater risk of poor outcomes and may require additional monitoring and dose adjustment.

Inflammation is associated with voriconazole trough concentrations.

Voriconazole concentrations display a large variability, which cannot completely be explained by known factors. Inflammation may be a contributing factor, as inflammatory stimuli can change the activities and expression levels of cytochrome P450 isoenzymes. We explored the correlation between inflammation, reflected by C-reactive protein (CRP) concentrations, and voriconazole trough concentrations. A retrospective chart review of patients with at least one steady-state voriconazole trough concentration and a CRP concentration measured on the same day was performed. A total of 128 patients were included. A significantly (P < 0.001) higher voriconazole trough concentration was observed in patients with severe inflammation (6.2 mg/liter; interquartile range [IQR], 3.4 to 8.7 mg/liter; n = 20) than in patients with moderate inflammation (3.4 mg/liter; IQR, 1.6 to 5.4 mg/liter; n = 60) and in patients with no to mild inflammation (1.6 mg/liter; IQR, 0.8 to 3.0 mg/liter; n = 48). The patients in all three groups received similar voriconazole doses based on mg/kg body weight (P = 0.368). Linear regression analyses, both unadjusted and adjusted for covariates of gender, age, dose, route of administration, liver enzymes, and interacting coadministered medications, showed a significant association between voriconazole and CRP concentration (P < 0.001). For every 1-mg/liter increase in the CRP concentration, the voriconazole trough concentration increased by 0.015 mg/liter (unadjusted 95% confidence interval [CI], 0.011 to 0.020 mg/liter; adjusted 95% CI, 0.011 to 0.019 mg/liter). Inflammation, reflected by the C-reactive protein concentration, is associated with voriconazole trough concentrations. Further research is necessary to assess if taking the inflammatory status of a patient into account is helpful in therapeutic drug monitoring of voriconazole to maintain concentrations in the therapeutic window, thereby possibly preventing suboptimal treatment or adverse events.

Understanding variability with voriconazole using a population pharmacokinetic approach: implications for optimal dosing

Voriconazole exhibits highly variable, non-linear pharmacokinetics and is associated with a narrow therapeutic range. This study aimed to investigate the population pharmacokinetics of voriconazole in adults, including the effect of CYP2C19 genotype and drug-drug interactions. Non-linear mixed effects modelling (NONMEM) was undertaken of six voriconazole studies in healthy volunteers and patients. Dosing simulations to examine influential covariate effects and voriconazole target attainment (2-5 mg/L) stratified by CYP2C19 phenotype were performed. We analysed 3352 voriconazole concentration measurements from 240 participants. A two-compartment pharmacokinetic model with first-order oral absorption with lag time and Michaelis-Menten elimination best described voriconazole pharmacokinetics. Participants with one or more CYP2C19 loss-of-function (LoF) alleles had a 41.2% lower Vmax for voriconazole. Co-administration of phenytoin or rifampicin, St John's wort or glucocorticoids significantly increased voriconazole elimination. Among patients receiving 200 mg of voriconazole twice daily, predicted trough concentrations on day 7 were <2 mg/L for oral and intravenous regimens for 72% and 63% of patients without CYP2C19 LoF alleles, respectively, with 49% and 35% below this threshold with 300 mg twice daily dosing. Conversely, these regimens resulted in 29%, 39%, 57% and 77% of patients with CYP2C19 LoF alleles with voriconazole trough concentrations ≥5 mg/L. Current dosing regimens for voriconazole result in subtherapeutic exposure in many patients without CYP2C19 LoF alleles, suggesting the need for higher doses, whereas these regimens result in supratherapeutic exposure in a high proportion of patients with reduced CYP2C19 activity. These findings support the essential role of therapeutic drug monitoring in ensuring efficacious and safe voriconazole exposure.

Therapeutic drug monitoring of voriconazole: a case report of multiple drug interactions in a patient with an increased CYP2C19 activity.

BackgroundVoriconazole is metabolized by cytochrome P450 (CYP) 2C19 and CYP 3A4. Drug-drug interactions and genetic polymorphisms modulate their activities.Case presentationA 35-year old African female patient with resistant HIV and a cerebral mass of unknown origin was treated with voriconazole for a suspicion of disseminated Aspergillosis infection. Voriconazole trough concentrations (C0) were within target range while the patient was under esomeprazole, a CYP2C19 inhibitor. Phenotyping showed decreased CYP2C19 activity, whereas genotyping showed a variant allele associated with increased enzyme activity. The patient was switched to ranitidine because of the introduction of atazanavir. CYP3A4 inhibition by atazanavir combined with uninhibited CYP2C19 activity resulted in subtherapeutic voriconazole C0. The reintroduction of esomeprazole allowed restoring voriconazole C0 back to target range.ConclusionThe integration of drug-drug interactions and pharmacogenetics data is crucial to interpret drug concentrations correctly, thus preventing suboptimal exposure to voriconazole.

Association of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity

BackgroundTherapeutic drug monitoring (TDM) of voriconazole is important to optimize efficacy and to minimize toxicity and intolerance. In this study, we evaluated the effect of sustained high plasma trough concentration of voriconazole on the incidence of hepatotoxicity in hospitalized Japanese patients. MethodsThirty-nine patients were divided into 3 groups according to trough concentrations in two consecutive TDMs: <4μg/ml in the first TDM (group A, n=25), >4μg/ml in the first and <4μg/ml in the second TDM (group B, n=8), and >4μg/ml in both first and second TDMs (group C, n=6). ResultsIncidences of hepatotoxicity in groups A, B and C were 16.0, 25.0 and 83.3%, and significant differences were observed between groups A and C and groups B and C. Multiple logistic regression analysis identified the classification into groups A, B and C as an independent variable of hepatotoxicity. ConclusionsThese results suggest that sustained high trough concentration of voriconazole may increase the risk of hepatotoxicity, and decreasing trough concentration to <4μg/ml by dose adjustment after the initial TDM may reduce the incidence of hepatotoxicity in patients treated with voriconazole.

The incidence of invasive fungal infections in neutropenic patients with acute leukemia and myelodysplastic syndromes receiving primary antifungal prophylaxis with voriconazole

The objective of this study is to characterize the outcomes of primary antifungal prophylaxis with voriconazole in patients receiving intensive chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS). We conducted a single center, retrospective, cohort study of consecutive adult patients with AML or MDS at Mayo Clinic between January 1, 2006 and July 1, 2010. The study included patients undergoing induction or first relapse combination chemotherapy who received voriconazole 200 mg orally twice daily as prophylaxis during the neutropenic phase. Patient records were evaluated until 30 days after neutrophil recovery for development of invasive fungal infection (IFI) as defined per EORTC/MSG 2008 criteria with computed tomography scans independently reviewed by a radiologist. Therapeutic drug monitoring and reasons for voriconazole discontinuation were documented. Twenty four episodes of IFI were detected among 165 consecutive patients for an overall incidence of 145 per 1000 patients. The incidence of IFI was 24, 42, and 78 per 1000 patients for proven, probable, and possible infection, respectively. Four patients developed proven IFI (n = 2 Aspergillus spp., n = 2 Rhizopus spp.). Serum voriconazole trough concentrations were available in 39 patients, and no statistically significant difference in voriconazole trough level was observed between those with versus without an IFI. Voriconazole prophylaxis was discontinued in 81 patients due to suspected IFI (n = 24), fever of unknown origin (n = 19), adverse events (n = 23), and other causes (n = 17). Voriconazole as primary IFI prophylaxis is safe and may be beneficial in AML/MDS patients receiving intensive chemotherapy.

The Development of Appropriate Dosage of Anti-bacterial and Anti-fungal Agents Based on Pharmacokinetics and Pharmacodynamics

An initial loading procedure has been recommended to enable teicoplanin to promptly reach an effective serum concentration for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). The mean trough concentrations were 13.2 mg/L for patients with eradication of MRSA. I showed that the administration of ≥36 mg/kg during the first 3 days was effective in promptly obtaining a trough concentration target of ≥13 mg/L for the initial treatment of MRSA infections. The major adverse effect associated with linezolid treatment is reversible myelosuppression, primarily thrombocytopenia. I demonstrated that the incidence of linezolid-induced thrombocytopenia was higher among patients with renal failure than in patients with normal renal function. A statistically significant (p<0.01) and strong correlation (r=0.933) was observed between linezolid and creatinine clearance. A negative correlation (r=-0.567) was also shown between linezolid clearance and blood urea nitrogen. Voriconazole trough plasma concentration has been reported to correlate with hepatotoxicity. Logistic regression analysis revealed that the therapeutic range for the voriconazole trough concentration should be 2-4 mg/L. Nonlinear pharmacokinetic analysis suggested that voriconazole therapy should be initiated with a dose of 7.2-8.9 mg/kg/day for CYP2C19 wild type and 4.4-6.5 mg/kg/day for the non-wild type in patients. Anaemia and thrombocytopenia are major side effects of liposomal amphotericin B. I demonstrated that the doses of liposomal amphotericin B estimated to cause side effects of a low red blood cell count, anaemia and thrombocytopenia with 50% probability are 4.0, 3.3 and 3.0 mg/kg/day, respectively.

Evaluation of the effect of obesity on voriconazole serum concentrations

Voriconazole is a second-generation triazole antifungal, approved by the FDA in 2002. Despite a decade of experience with voriconazole, there are limited published data analysing serum concentrations and toxicity in obese patients. Therefore, we evaluated voriconazole trough serum concentrations in obese and normal-weight patients in a retrospective cohort study. Voriconazole serum trough concentrations and toxicities were compared for obese (body mass index >35 kg/m(2)) versus normal-weight (body mass index 18.5-24.9 kg/m(2)) patients receiving 4 mg/kg voriconazole every 12 h. The obese group (n = 21) had significantly higher mean serum voriconazole trough concentrations than the normal-weight group (n = 66) (6.2 and 3.5 mg/L, respectively, P < 0.0001). Patients in the obese group also had higher rates of supratherapeutic voriconazole levels (>5.5 mg/L) than patients in the normal-weight group (67% versus 17%, respectively, P < 0.0001). However, hepatotoxicity and neurotoxicity rates did not differ between groups. The secondary endpoint compared mean serum voriconazole concentrations in the obese population when dosed at 4 mg/kg based on ideal body weight, adjusted body weight and actual body weight, which were statistically significantly different at 3.95, 3.3 and 6.2 mg/L, respectively (P = 0.0009). Therapeutic voriconazole concentrations (2.0-5.5 mg/L) occurred in 29% of obese patients when dosed on actual body weight, and 45% and 80% of patients when dosed on ideal body weight and adjusted body weight, respectively. Our results suggest a strong association between supratherapeutic concentrations and morbidly obese patients when dosed at 4 mg/kg actual body weight. Dosing voriconazole based on an ideal body weight or adjusted body weight may be appropriate for morbidly obese patients.

Multicenter Study of Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring

Voriconazole is a first-line agent in the treatment of many invasive fungal infections and is known to display highly variable pharmacokinetics. Previous studies of voriconazole therapeutic drug monitoring (TDM) have suggested concentration monitoring to be clinically useful but have been limited by small patient samples at a single institution. This multicenter retrospective study aimed to investigate relationships between voriconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect voriconazole concentration. Medical records were reviewed for patients who received voriconazole and had at least 1 concentration measured at seven hospitals in Australia. The study included 201 patients with 783 voriconazole trough concentrations. Voriconazole concentrations of <1.7 mg/liter were associated with a significantly greater incidence of treatment failure (19/74 patients [26%]) than concentrations of ≥1.7 mg/liter (6/89 patients [7%]) (P < 0.01). Neurotoxic adverse events (visual and auditory hallucinations) occurred more frequently at voriconazole concentrations of >5 mg/liter (10/31 patients [32%]) than at concentrations of ≤5 mg/liter (2/170 patients [1.2%]) (P < 0.01). Multiple regression analysis of voriconazole concentration identified associations between increasing patient weight, oral administration of voriconazole, and coadministration of phenytoin or rifampin and significantly reduced concentrations, and associations between increasing patient age and coadministration of proton pump inhibitors and increased concentrations. Coadministration of glucocorticoids was found to significantly reduce voriconazole concentrations, inferring a previously unreported drug interaction between glucocorticoids and voriconazole.

COMMENTARY

COMMENTARY

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

Voriconazole-related severe adverse events: clinical application of therapeutic drug monitoring in Korean patients

Voriconazole is a triazole agent with excellent antifungal activity against Aspergillus species. However, despite its potential advantages, the occurrence of unpredictable toxicities might be critical in immunocompromised patients. The aim of this study was to analyze risk factors for voriconazole-related severe adverse events (SAEs). This prospective observational study was conducted in Korean patients with hematological malignancies and invasive aspergillosis on intravenous voriconazole therapy between June 2008 and April 2009. Of the 25 patients enrolled, eight (32%) showed voriconazole-related SAEs, which included hepatotoxicities (n=5), cardiac tachyarrhythmias (n=2), and neurotoxicity (n=1). Sex, age, underlying hematological malignancies, voriconazole dose, the co-administration of a proton pump inhibitor, and CYP2C19 genotype were not found to be related to the occurrence of SAEs. However, trough plasma concentrations of voriconazole were found to be significantly higher in the patients with an SAE: median 6.32 mg/l (interquartile range (IQR) 2.86-9.71 mg/l) vs. median 2.15 mg/l (IQR 0.92-4.00 mg/l); p=0.011. Receiver operating characteristic curve analysis identified a cut-off trough concentration for SAEs of 5.83 mg/l (sensitivity 62.5% and specificity 94.1%). Furthermore, multivariate analysis showed that a trough concentration of ≥ 5.83mg/l was the only significant independent risk factor of an SAE. This study shows that therapeutic drug monitoring is indicated in patients with a voriconazole-related SAE and that dose adjustment is required if the trough concentration of voriconazole exceeds 5.83 mg/l.

Therapeutic Drug Monitoring of Voriconazole After Intravenous Administration in Infants and Children With Primary Immunodeficiency

A voriconazole trough concentration (Ctrough) <1 mg/L is associated with a higher risk of treatment failure. The aim of this work was to describe the probability of not achieving this target concentration in infants and children receiving intravenous voriconazole. Voriconazole trough concentrations obtained during routine therapeutic drug monitoring over a 5-year period were collected retrospectively from infants and children receiving intravenous voriconazole for presumed or proven invasive fungal infections. Sixty-two trough concentrations were obtained from 6 infants and 10 children. The risk of a Ctrough <1 mg/L was 77% and 47%, respectively. Daily doses between 20 and 32 mg/kg were necessary in some patients to achieve a Ctrough >1 mg/L, compared with the currently recommended 14-mg/kg regimen. Routine therapeutic drug monitoring is potentially helpful in infants and children receiving voriconazole, even intravenously.

Impact of Therapeutic Drug Monitoring of Voriconazole in a Pediatric Population

Voriconazole trough concentrations more than 1 mg/L are associated with a higher likelihood of success. It is unknown whether these trough concentrations are reached with the current recommended pediatric dosing schedule. We retrospectively analyzed the results of our therapeutic drug monitoring service for voriconazole in 18 children treated at our children's hospital. Thirty-nine voriconazole plasma concentrations were measured. In 44% of patients, the first voriconazole concentration was below the target. Dose adjustment eventually resulted in plasma concentrations within the predefined target range in all patients. Given the high proportion of patients with subtherapeutic concentrations, monitoring plasma concentrations should be performed routinely in pediatric patients receiving voriconazole.

Niveau de preuve du suivi thérapeutique pharmacologique du voriconazole

Voriconazole is a major antifungal drug with activity against endemic fungi, Candida and Aspergillus species in immunocompromised patients. Voriconazole has a good bioavailability, an high protein binding percentage in plasma and is metabolized in liver via CYP2C19. It presents important neuro- and hepatotoxicities. Some studies determined trough concentrations of voriconazole in plasma using liquid chromatography coupled with UV or tandem mass detection. These studies showed a relationship between trough concentrations of voriconazole and efficacy or toxicity. Indeed, some studies reported a relationship between a lack of clinical response and concentrations below 1 or 2 μg/mL according to the localization of infection, while toxicities are frequently observed at concentrations above 5 μg/mL. Some particular populations will have to be taken into account such as children, patients with hemodialysis-dependent renal deficiency or hepatic insufficiency, cystic fibrosis patients or those treated concomitantly with interfering drugs. According to our survey, therapeutic drug monitoring of voriconazole appears recommended. However, controlled studies are still necessary to validate it prospectively and to evaluate pharmacokinetically-based methods proposed for individual dose adjustment.

Monitoring Trough Concentration of Voriconazole Is Important to Ensure Successful Antifungal Therapy and to Avoid Hepatic Damage in Patients with Hematological Disorders.

Abstract 4731Fungal infection is a life threatening complication in patients with hematological disorders. Although initial therapy with voriconazole has been shown to be the most effective approach for patients with definitive invasive aspergillosis, the reported effectiveness of voriconazole is not satisfactory and the reasons for treatment failure have not been elucidated. We hypothesized that voriconazole concentration is one of the critical factors that determine the efficacy, and we investigated the role of therapeutic dose monitoring (TDM) in the treatment of fungal infections with voriconazole through 49 analyses from 34 patients who received treatment for hematologic diseases at Tokyo University Hospital, Japan, between February 2007 and July 2008. The cases included proven (N=1), probable (N=5), and possible (N=29) fungal infections according to the 2008 EORTC/MSG criteria, and empirically treated cases (N=15). First, weak correlation was found between administered dosage (per patient weight) and trough concentration (coefficient of determination: r2=0.058). Then we explored patient-specific parameters that would help to predict voriconazole concentrations. However, none of renal function (determined by glomerular filtration rate), bilirubin level, and patient age, and administration route had significant effect on TDM. We also evaluated intra-patient dose concentration relationship. Eight out of 10 patients who had voriconazole dosage increased according to the previous TDM demonstrated higher concentration, but two patients did not show elevation of voriconazole concentration despite dose escalation. Next, we evaluated the outcome of anti-fungal therapy with the composite assessment system where patients were assumed non-responders when they failed to show improvement in at least 2 of the following 3 criteria: clinical, radiologic, and mycologic. Fever resolution after voriconazole therapy was observed in eleven out of 32 cases (34%). Improvement of CT findings was shown in 16 out of 46 cases (35%, no radiological finding was observed in three cases). More specifically, cases which showed nodular shadow in chest CT revealed 41% (13 out of 32 cases) of improvement of CT findings and cases which showed halo sign revealed 44% (four out of nine cases). Using the composite outcome assessment, there was no definite correlation between voriconazole TDM and efficacy. However, when we conducted a sub-population analysis where subjects with refractory underlying hematological diseases were omitted, voriconazole concentration was significantly correlated with the efficacy. Concretely, none of the cases with TDM> 2 mg/L failed to respond to voriconazole while two out of six cases with TDM below this threshold were non-responders. This indicates that 2 mg/L is the lower limit of voriconazole TDM to ensure adequate efficacy. On the other hand, high concentration of voriconazole was associated with liver toxicity. Concretely, eight out of 11 cases with TDM > 6 mg/L were associated with elevation of hepatic enzyme.In conclusion, we concluded that (1) TDM should be executed and targeted to 2-6 mg/L to improve efficacy and to avoid side effects, (2) it is difficult to predict voriconazole concentration and it should be measured when responses were inadequate, (3) dose escalation is not always effective to elevate voriconazole concentration and TDM should be repeated after dose modifications. Disclosures:No relevant conflicts of interest to declare.

Phenytoin‐induced reduction of voriconazole serum concentration is not compensated by doubling the dosage

Phenytoin‐induced reduction of voriconazole serum concentration is not compensated by doubling the dosage

Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders

We investigated the role of therapeutic dose monitoring (TDM) in the treatment of fungal infections with voriconazole through 49 analyses of 34 patients who received treatment for hematologic diseases. Voriconazole concentration was highly variable among patients regardless of renal, liver functions, or age, and the effect of dose enhancement was not constant. This indicates the difficulty of predicting voriconazole concentration without TDM. We evaluated the outcome with the composite assessment system where patients were assumed non-responders when they failed to show improvement in at least 2 of the following 3 criteria: clinical, radiologic, and mycologic. We showed that concentration-response relationship depended on the status of underlying hematologic diseases; this relationship was observed only in cases without refractory hematologic diseases, but not in those with refractory diseases. In the former group, cases with >2 mg/L of concentration were associated with good response to voriconazole. On the other hand, elevation of hepatic enzyme was frequently observed when voriconazole concentration was >6 mg/L. From these results, we concluded that TDM should be executed and targeted to 2-6 mg/L to improve efficacy and to avoid side effects.

Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes

Voriconazole metabolism is mostly mediated via the cytochrome P450 (CYP) 2C19 isozyme. The non-wild (mutant) type of CYP2C19 is generally found in 60–70% of Asian populations. Because the voriconazole trough plasma concentration has been reported to correlate with hepatotoxicity, this study investigated the effect of CYP2C19 polymorphism on the relationship between voriconazole trough concentrations and liver function abnormalities in 29 Japanese patients with fungal infections (CYP2C19 wild-type, n = 10; non-wild-type, n = 19). Hepatotoxicity, defined as liver enzyme abnormality according to the National Cancer Institute criteria, was observed in 10 (34.5%) of 29 patients with a trough concentration ≥3.9 mg/L. Logistic regression analysis suggested that the therapeutic range for the voriconazole trough concentration should be 2–4 mg/L. Non-linear pharmacokinetic analysis suggested that voriconazole therapy should be initiated with a dose of 7.2–8.9 mg/kg/day for CYP2C19 wild-type and 4.4–6.5 mg/kg/day for the non-wild-type in Japanese patients. These recommended initial dosages and subsequent dose adjustment for the target concentration range by therapeutic drug monitoring should avoid adverse events and thus enable continued effective voriconazole therapy for Japanese patients with mycoses.