Voriconazole trough concentration and hepatotoxicity in patients with low serum albumin

Hirata, Atsushi; Noto, Keisuke; Ota, Ryosuke; Yokoyama, S.; Hosomi, Kouichi; Takada, Mitsutaka; Matsuoka, Hiroshi

doi:10.5414/cp203345

Cited by 17 publications

(13 citation statements)

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“…Kang et al found that ALT is a significant factor affecting VRZ concentration, in agreement with our results [32]. Although there is substantial evidence linking AST and VRZ concentration, we found no significant effect of AST in our model [33][34][35]. There are possible explanations for this.…”

Section: Discussionsupporting

confidence: 91%

“…There are possible explanations for this. Most of the previous studies were limited to specific populations, such as patients with low serum albumin [34] or hematological malignancies [35]. The other reason may be differing pharmacokinetic characteristics such as the clearance and the volume of distribution among populations [36,37], which were reported to have different influence factors such as platelet count, age, and CYP2C19 phenotype.…”

Section: Discussionmentioning

confidence: 99%

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A Large Sample Retrospective Study on the Distinction of Voriconazole Concentration in Asian Patients from Different Clinical Departments

et al. 2021

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Voriconazole (VRZ) is widely used to prevent and treat invasive fungal infections; however, there are a few studies examining the variability and influencing the factors of VRZ plasma concentrations across different clinical departments. This study aimed to evaluate distinction of VRZ concentrations in different clinical departments and provide a reference for its reasonable use. From 1 May 2014 to 31 December 2020, VRZ standard rates and factors affecting the VRZ trough concentration were analyzed, and a multiple linear regression model was constructed. The standard rates of VRZ in most departments were above 60%. A total of 676 patients with 1212 VRZ trough concentrations using a dosing regimen of 200 mg q12h from seven departments were enrolled in the correlation analysis. The concentration distribution varied significantly among different departments (p < 0.001). Fifteen factors, including department, CYP2C19 phenotype, and gender, correlated with VRZ concentration. A multiple linear regression model was established as follows: VRZ trough concentration = 5.195 + 0.049 × age + 0.007 × alanine aminotransferase + 0.010 × total bilirubin − 0.100 × albumin − 0.004 × gamma-glutamyl transferase. According to these indexes, we can predict possible changes in VRZ trough concentration and adjust its dosage precisely and individually.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

A Large Sample Retrospective Study on the Distinction of Voriconazole Concentration in Asian Patients from Different Clinical Departments

et al. 2021

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“…Another possible explanation is that patients with malignant hematological diseases are prone to nausea and vomiting after chemotherapy. We also found a negative correlation between ALB and voriconazole concentration as reported by previous study 28 . Accordingly, we should be more alert to the effect of ALB levels on voriconazole concentrations, especially in patients with low serum albumin.…”

Section: Discussionsupporting

confidence: 91%

Population Pharmacokinetics and Factors Influencing Trough Concentration of Voriconazole in Children with Hematological Malignancies

et al. 2022

Preprint

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Aim: This prospective study aims to investigate the factors influencing voriconazole trough concentration (Cmin), develop a population pharmacokinetics (PPK) model and recommend an appropriate voriconazole dosing regimen for children with hematological malignancies. Methods: Prospectively enrolled a total of 70 children aged <18 years and 149 samples. The factors influencing voriconazole Cmin were analyzed by univariate analysis and multiple linear regression analysis. Nonlinear mixed effects modeling (NONMEM) was applied to establish the PPK model. Dosage simulation based on albumin (ALB) levels and CYP2C19 genotype. Results: Multiple linear regression results demonstrated that route of administration, ALB and concomitant administration with glucocorticoid (GLU) and proton pump inhibitors (PPIs) were significant factors of voriconazole Cmin. A one-compartment model could best describe the pharmacokinetics of voriconazole. The extensive metabolizers (EM), ALB were significant covariates of clearance (CL). The typical value of CL, the volume of distribution (V) and oral bioavailability (F) were 1.52 L/h, 35.7 L and 0.909, respectively. The recommended dosing regimens for EM patients with ALB level of 20.0~35.0 g/L, 35.1~45.0 g/L and 45.1~55.0 g/L were4, 8 and 12 mg/kg intravenously or orally twice daily, respectively, and were 2, 4 and 7 mg/kg by intravenous or oral administration twice daily for non-EM. Conclusion: We found that route of administration, ALB and co-administration of GLU and PPI had quantitative relationships with voriconazole Cmin. The combination of CYP2C19 genotype and ALB levels to determine the initial dosing regimen of voriconazole could provide a reference for individualized treatment in children with hematological malignancies.

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“…Moreover, since almost all of the patients in our study took the same dose of voriconazole, the Michaelis–Menten equation could not be clearly demonstrated. Dote et al [ 29 ] and Hirata et al [ 35 ] found hypoalbuminemia to be associated with decreasing clearance of voriconazole, therefore, toxic vigilance is important in patients with low albumin.…”

Section: Discussionmentioning

confidence: 99%

Impact of Albumin and Omeprazole on Steady-State Population Pharmacokinetics of Voriconazole and Development of a Voriconazole Dosing Optimization Model in Thai Patients with Hematologic Diseases

et al. 2020

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This study aimed to identify factors that significantly influence the pharmacokinetics of voriconazole in Thai adults with hematologic diseases, and to determine optimal voriconazole dosing regimens. Blood samples were collected at steady state in 65 patients (237 concentrations) who were taking voriconazole to prevent or treat invasive aspergillosis. The data were analyzed using a nonlinear mixed-effects modeling approach. Monte Carlo simulation was applied to optimize dosage regimens. Data were fitted with the one-compartment model with first-order absorption and elimination. The apparent oral clearance (CL/F) was 3.43 L/h, the apparent volume of distribution (V/F) was 47.6 L, and the absorption rate constant (Ka) was fixed at 1.1 h−1. Albumin and omeprazole ≥ 40 mg/day were found to significantly influence CL/F. The simulation produced the following recommended maintenance doses of voriconazole: 50, 100, and 200 mg every 12 h for albumin levels of 1.5–3, 3.01–4, and 4.01–4.5 g/dL, respectively, in patients who receive omeprazole ≤ 20 mg/day. Patients who receive omeprazole ≥ 40 mg/day and who have serum albumin level 1.5–3 and 3.01–4.5 g/dL should receive voriconazole 50 and 100 mg, every 12 h, respectively. Albumin level and omeprazole dosage should be carefully considered when determining the appropriate dosage of voriconazole in Thai patients.

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Voriconazole trough concentration and hepatotoxicity in patients with low serum albumin

Cited by 17 publications

References 0 publications

A Large Sample Retrospective Study on the Distinction of Voriconazole Concentration in Asian Patients from Different Clinical Departments

A Large Sample Retrospective Study on the Distinction of Voriconazole Concentration in Asian Patients from Different Clinical Departments

Population Pharmacokinetics and Factors Influencing Trough Concentration of Voriconazole in Children with Hematological Malignancies

Impact of Albumin and Omeprazole on Steady-State Population Pharmacokinetics of Voriconazole and Development of a Voriconazole Dosing Optimization Model in Thai Patients with Hematologic Diseases

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