Voriconazole therapeutic drug monitoring and hepatotoxicity in critically ill patients: A nationwide multi-centre retrospective study

Wang, Taotao; Miao, Lei; Shao, Hua; Wei, Xiaohua; Yan, Miao; Zuo, Xiaoxia; Zhang, Jun; Hai, Xin; Fan, Guangjun; Wang, Wei; Hu, Linlin; Zhou, Jing; Zhao, Yang; Wang, Jingjing; Guo, Sixun; Liu, Jin; Li, Hao; Liu, Hui; Wang, Quan-Fang; Chen, Jiaojiao; Li, Sihan; Dong, Yalin

doi:10.1016/j.ijantimicag.2022.106692

Cited by 13 publications

(8 citation statements)

References 38 publications

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“…Our data indicated that dose adjustments should be based on CYP2C19 phenotype, body weight, and drug susceptibility testing. However, such adjustment is not an adequate substitute for therapeutic drug monitoring (TDM) because other factors (ie, liver function, drug interactions, the site of infection, and comorbidities) can also influence VRC exposure 36–40 . Therefore, dose adjustments should be combined with TDM to reduce the risk of adverse reactions.…”

Section: Discussionmentioning

confidence: 99%

“…However, such adjustment is not an adequate substitute for therapeutic drug monitoring (TDM) because other factors (ie, liver function, drug interactions, the site of infection, and comorbidities) can also influence VRC exposure. [36][37][38][39][40] Therefore, dose adjustments should be combined with TDM to reduce the risk of adverse reactions. Furthermore, risk-benefit analysis should be performed in combination with the patient's actual situation.…”

Section: Discussionmentioning

confidence: 99%

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Optimization of Voriconazole Dosing Regimens Against Aspergillus Species and Candida Species in Pediatric Patients After Hematopoietic Cell Transplantation: A Theoretical Study Based on Pharmacokinetic/Pharmacodynamic Analysis

Xie

Jiang

Qiu

et al. 2023

The Journal of Clinical Pharma

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This study aimed to optimize the dosing regimens of voriconazole (VRC) for pediatric patients after hematopoietic cell transplantation with different cytochrome P450 (CYP) 2C19 phenotypes and body weights, based on pharmacokinetic (PK)/pharmacodynamic (PD) analysis. The PK parameters of VRC were derived from previous literature. Combined with key factors affecting VRC, patients were categorized into 9 subgroups based on different CYP2C19 phenotypes (poor metabolizer/intermediate metabolizer, normal metabolizer, and rapid metabolizer/ultrarapid metabolizer) and typical body weights (15, 40, and 65 kg). Monte Carlo simulation was used to investigate dosing regimens for different groups. The area under the 24‐hour free drug concentration–time curve to the minimum inhibitory concentration (MIC) > 25 was used as the target value for effective treatment. The probability of target achievement and the cumulative fraction of response were determined on the basis of the assumed MICs and MICs distribution frequency of Aspergillus species and Candida species. When the MIC was ≤1 mg/L, 4 mg/kg every 12 hours was sufficient for optimal effects in groups 1‐3 and groups 5 and 6; however, 6 mg/kg every 12 hours was required for group 4, and 8 mg/kg every 12 hours was required for groups 7‐9. In empirical treatment, lower (2‐6 mg/kg every 12 hours) and higher (6‐12 mg/kg every 12 hours) dosing regimens were recommended for Candida spp. and Aspergillus spp., respectively. Our findings will assist in selecting appropriate dosing regimens of VRC for pediatric patients after hematopoietic cell transplantation with different CYP2C19 phenotypes and body weights. Clinically, it is better to continuously adjust the dosing on the basis of the therapeutic drug monitoring.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Optimization of Voriconazole Dosing Regimens Against Aspergillus Species and Candida Species in Pediatric Patients After Hematopoietic Cell Transplantation: A Theoretical Study Based on Pharmacokinetic/Pharmacodynamic Analysis

Xie

Jiang

Qiu

et al. 2023

The Journal of Clinical Pharma

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“…2 There was increasing evidence of a significant correlation between hepatotoxicity and voriconazole trough concentrations. [3][4][5] But voriconazole plasma concentrations present wide interpatient variability, primarily due to gene polymorphism of cytochrome P450 (CYP) 2C19. 6 High voriconazole trough concentrations are more likely to be observed in poor metabolizers than in normal metabolizers, with an increased risk of hepatotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Voriconazole-Induced Hepatotoxicity in a Patient with Pulmonary Aspergillosis: A Case Report

Gu,

Ai,

Pang

et al. 2023

IDR

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Voriconazole is the therapy of choice for aspergillosis. However, hepatotoxicity is the most common reason for the discontinuation of voriconazole. In contrast, posaconazole is well tolerated, with a low incidence of hepatotoxicity. In most cases, hepatotoxicity is associated with high voriconazole trough concentration influenced mainly by cytochrome P450 (CYP) 2C19 gene polymorphism. Compared with normal metabolizers, intermediate and poor metabolizers generally have higher voriconazole trough concentrations with an increased risk of hepatotoxicity. Here, we describe changes in hepatotoxicity throughout azole therapy in a patient with pulmonary aspergillosis (PA). Nevertheless, the patient with the normal metabolism genotype of CYP2C19 developed severe hepatotoxicity caused by voriconazole but tolerated posaconazole well, with a lack of direct cross-hepatotoxicity between the both. Interestingly, the patient had a high risk of hepatotoxicity at a low voriconazole trough concentration. Fortunately, elevated liver enzymes declined to the baselines with posaconazole treatment.

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“…On the other hand, supratherapeutic plasma trough concentrations (>5 mg/L) were observed to increase the probability of neurotoxicity, visual disturbance, and hepatotoxicity. [7][8][9] Enhanced attention to therapeutic drug monitoring (TDM) and personalized medication management is crucial because of the limited therapeutic range exhibited by voriconazole. 10,11 Several studies have demonstrated that age plays a crucial role in the pharmacokinetics of voriconazole.…”

mentioning

confidence: 99%

“…A multicenter retrospective study conducted by Dolton et al revealed that inadequate trough concentrations (<2 mg/L) resulted in a significantly lower response rate, based on clinical and radiological parameters. On the other hand, supratherapeutic plasma trough concentrations (>5 mg/L) were observed to increase the probability of neurotoxicity, visual disturbance, and hepatotoxicity 7–9 . Enhanced attention to therapeutic drug monitoring (TDM) and personalized medication management is crucial because of the limited therapeutic range exhibited by voriconazole 10,11 …”

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confidence: 99%

Population Pharmacokinetics of Voriconazole and Dose Optimization in Elderly Chinese Patients

Wang,

Shen,

et al. 2023

The Journal of Clinical Pharma

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Voriconazole is commonly recommended as a first‐line therapy for invasive aspergillosis infections. The elderly patients are susceptible to infectious diseases owing to their decreased physical function and immune system. Our study aims to establish a population‐based pharmacokinetic model for receiving intravenous voriconazole of elderly patients, and to optimize dosing protocols through a simulated approach. An accurate fit to the concentration‐time profile of voriconazole was achieved by employing a one‐compartment model featuring first‐order elimination. The typical clearance rate of voriconazole was found to be 3.22 L/h, with a typical volume of distribution of 194 L. The covariate analysis revealed that albumin (ALB), gamma glutamyl transpeptidase, and direct bilirubin had significant impacts on voriconazole clearance. Additionally, the body weight was found to be associated with the volume. Individualized dosing regimens were recommended for different ALB levels based on population PK model prediction. The proposed dosing regimens could provide a rationale for dosage individualization, improve the clinical outcomes and minimize drug‐related toxicities.This article is protected by copyright. All rights reserved

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Voriconazole therapeutic drug monitoring and hepatotoxicity in critically ill patients: A nationwide multi-centre retrospective study

Cited by 13 publications

References 38 publications

Optimization of Voriconazole Dosing Regimens Against Aspergillus Species and Candida Species in Pediatric Patients After Hematopoietic Cell Transplantation: A Theoretical Study Based on Pharmacokinetic/Pharmacodynamic Analysis

Optimization of Voriconazole Dosing Regimens Against Aspergillus Species and Candida Species in Pediatric Patients After Hematopoietic Cell Transplantation: A Theoretical Study Based on Pharmacokinetic/Pharmacodynamic Analysis

Voriconazole-Induced Hepatotoxicity in a Patient with Pulmonary Aspergillosis: A Case Report

Population Pharmacokinetics of Voriconazole and Dose Optimization in Elderly Chinese Patients

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