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

Liu, Yang; Qiu, Tingting; Liang, Yan; Wang, Jijun; Hu, Kai; Bao, Fang; Zhang, Chao

doi:10.1016/j.clinthera.2019.04.027

Cited by 22 publications

(32 citation statements)

References 37 publications

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“…The model which best described the PK profile of voriconazole was the one-compartment model with first-order absorption and elimination, which was consistent with previous studies [ 14 , 16 , 18 , 19 , 21 , 25 , 31 ]. However, Mangal et al characterized PK with one compartment with first-order absorption and Michaelis–Menten elimination [ 17 ].…”

Section: Discussionsupporting

confidence: 88%

“…Interpatient variability in the V/F could not be estimated due to inadequate blood samples during the distribution phase. The estimation of CL/F was 3.43 L/h, which was within the range of previously reported values in population analysis (range from 2.88 to 11.2 L/h) [ 14 , 16 , 18 , 19 , 21 , 22 , 25 ]. The estimation of V/F was 47.6 L, which was lower than the values observed in other populations.…”

Section: Discussionsupporting

confidence: 88%

“…Therefore, high variability in the PK of voriconazole can be caused by CYP2C19 polymorphism [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], and these gene polymorphisms cause variations in drug clearance. Clinical factors that have been reported to affect the PK of voriconazole include body weight [ 15 , 16 , 20 , 22 , 23 ], age [ 18 , 19 ], liver function [ 20 ], aspartate aminotransferase (AST) [ 14 ], direct bilirubin (DB) [ 24 ], and voriconazole taken concurrently with CYP2C19 inducers (rifampin) [ 13 , 25 ], and inhibitors (proton pump inhibitors; PPIs) [ 17 ]. PPIs are commonly prescribed in patients with hematologic diseases to treat or prevent gastroduodenal adverse effects from chemotherapy, thrombocytopenia, and high-dose glucocorticoids [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, there is no population PK study confirming this effect [ 12 ]. Population PK analysis is a strategy that can be employed to identify mean PK parameters and their variation, to identify significant covariates, and to establish the optimal dosage regimen of voriconazole [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…The prevalence of CYP2C19 poor metabolizer has been reported to be about 15–20% in the Asian population [ 30 ]. Interestingly, we found some different factors that influence the clearance of voriconazole between Chinese [ 19 ] and Korean patients [ 20 ]. However, there are no studies that have investigated the population PK of voriconazole in Thai patients.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Predictive Value of C‐Reactive Protein and Albumin for Temporal Within‐Individual Pharmacokinetic Variability of Voriconazole in Pediatric Patients Undergoing Hematopoietic Cell Transplantation

Takahashi

Jaber

Smith

et al. 2022

The Journal of Clinical Pharma

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Voriconazole is a widely used antifungal agent in immunocompromised patients, but its utility is limited by its variable exposure and narrow therapeutic index. Population pharmacokinetic (PK) models have been used to characterize voriconazole PK and derive individualized dosing regimens. However, determinants of temporal within-patient variability of voriconazole PK were not well established. We aimed to characterize temporal variability of voriconazole PK within individuals and identify predictive clinical factors. This study was conducted as a part of a single-institution, phase I study of intravenous voriconazole in children undergoing hematopoietic cell transplantation (NCT02227797). We analyzed voriconazole PK study data collected at week 1 and again at week 2 after the start of voriconazole therapy in 59 pediatric patients undergoing HCT (age <21 years). Population PK analysis using nonlinear mixed effect modeling was performed to analyze temporal within-individual variability of voriconazole PK by incorporating a between-occasion variability term in the model. A 2-compartment linear elimination model incorporating body weight and cytochrome P450 2C19 phenotype described the data. The ratio of individual voriconazole clearance between weeks 1 and 2 ranged from 0.11 to 3.3 (−9.1 to +3.3-fold change). Incorporation of covariate effects by serum C-reactive protein and albumin levels decreased between-occasion variability of clearance as compared to the model without them (coefficient of variation, 41.2% and 59.5%, respectively) and improved the model fit (P < .05). As significant covariates on voriconazole PK, C-reactive protein and albumin concentrations may potentially serve as useful biomarkers as part of therapeutic drug monitoring.

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

Cited by 22 publications

References 37 publications

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

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

Predictive Value of C‐Reactive Protein and Albumin for Temporal Within‐Individual Pharmacokinetic Variability of Voriconazole in Pediatric Patients Undergoing Hematopoietic Cell Transplantation

Population Pharmacokinetics of Voriconazole and Dose Optimization in Elderly Chinese Patients

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