Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization

Li, Sichan; Wu, Sanlan; Gong, Weiguo; Cao, Peng; Chen, Xin; Liu, Wanyu; Xiang, Liping; Wang, Yang; Huang, Jiangeng

doi:10.3389/fphar.2021.730826

Cited by 4 publications

(4 citation statements)

References 38 publications

(53 reference statements)

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“…The clearance of VRC in children was approximately three times higher compared to adults [ 21 ]. A previous report indicated the clearance of VRC was 1.91 L/h in adult patients [ 22 ]. Our final PPK model demonstrated that the typical value of clearance was 7.35 L/h and the CYP2C19 genotype was the most important factor affecting VRC clearance.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of voriconazole and the role of CYP2C19 genotype on treatment optimization in pediatric patients

Hu,

Huang,

Huang

et al. 2023

PLoS ONE

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The aim of this study was to evaluate factors that impact on voriconazole (VRC) population pharmacokinetic (PPK) parameters and explore the optimal dosing regimen for different CYP2C19 genotypes in Chinese paediatric patients. PPK analysis was used to identify the factors contributing to the variability in VRC plasma trough concentrations. A total of 210 VRC trough concentrations from 91 paediatric patients were included in the study. The median VRC trough concentration was 1.23 mg/L (range, 0.02 to 8.58 mg/L). At the measurement of all the trough concentrations, the target range (1.0~5.5 mg/L) was achieved in 52.9% of the patients, while subtherapeutic and supratherapeutic concentrations were obtained in 40.9% and 6.2% of patients, respectively. VRC trough concentrations were adjusted for dose (Ctrough/D), with normal metabolizers (NMs) and intermediate metabolizers (IMs) having significantly lower levels than poor metabolizers (PMs) (PN-P < 0.001, PI-P = 0.039). A one-compartment model with first-order absorption and elimination was suitable to describe the VRC pharmacokinetic characteristics. The final model of VRC PPK analysis contained CYP2C19 phenotype as a significant covariate for clearance. Dose simulations suggested that a maintenance dose of 9 mg/kg orally or 8 mg/kg intravenously twice daily was appropriate for NMs to achieve the target concentration. A maintenance dose of 9 mg/kg orally or 5 mg/kg intravenously twice daily was appropriate for IMs. Meanwhile, PMs could use lower maintenance dose and an oral dose of 6 mg/kg twice daily or an intravenous dose of 5mg/kg twice daily was appropriate. To increase the probability of achieving the therapeutic range and improving efficacy, CYP2C19 phenotype can be used to predict VRC trough concentrations and guide dose adjustments in Chinese pediatric patients.

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of voriconazole and the role of CYP2C19 genotype on treatment optimization in pediatric patients

Hu,

Huang,

Huang

et al. 2023

PLoS ONE

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“…VCZ is extensively metabolized in the liver by enzymes of cytochrome P450 (CYP450), comprising CYP2C19, CYP3A, and CYP2C9 subfamilies [ 38 ], which may present genetic polymorphism and their expression is affected, resulting in a phenotype of poor, intermediate, or rapid metabolizers [ 172 ]. CYP2C19 enzymes convert VCZ into its inactive metabolite, VCZ-N-oxide [ 173 ].…”

Section: Voriconazolementioning

confidence: 99%

Nanotechnology-Based Approaches for Voriconazole Delivery Applied to Invasive Fungal Infections

et al. 2023

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Invasive fungal infections increase mortality and morbidity rates worldwide. The treatment of these infections is still limited due to the low bioavailability and toxicity, requiring therapeutic monitoring, especially in the most severe cases. Voriconazole is an azole widely used to treat invasive aspergillosis, other hyaline molds, many dematiaceous molds, Candida spp., including those resistant to fluconazole, and for infections caused by endemic mycoses, in addition to those that occur in the central nervous system. However, despite its broad activity, using voriconazole has limitations related to its non-linear pharmacokinetics, leading to supratherapeutic doses and increased toxicity according to individual polymorphisms during its metabolism. In this sense, nanotechnology-based drug delivery systems have successfully improved the physicochemical and biological aspects of different classes of drugs, including antifungals. In this review, we highlighted recent work that has applied nanotechnology to deliver voriconazole. These systems allowed increased permeation and deposition of voriconazole in target tissues from a controlled and sustained release in different routes of administration such as ocular, pulmonary, oral, topical, and parenteral. Thus, nanotechnology application aiming to delivery voriconazole becomes a more effective and safer therapeutic alternative in the treatment of fungal infections.

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“…Individualized dose adjustment of VRZ may be necessary for different CYP2C19 genotypes. The proper dosage can be determined using TDM in conjunction with pharmacogenetic testing ( He et al, 2020 ; Li et al, 2021 ).…”

Section: The Impact Of Gene Polymorphisms On Vrzmentioning

confidence: 99%

The impact of gene polymorphism and hepatic insufficiency on voriconazole dose adjustment in invasive fungal infection individuals

Li,

Zhang

et al. 2023

Front. Genet.

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Voriconazole (VRZ) is a broad-spectrum antifungal medication widely used to treat invasive fungal infections (IFI). The administration dosage and blood concentration of VRZ are influenced by various factors, posing challenges for standardization and individualization of dose adjustments. On the one hand, VRZ is primarily metabolized by the liver, predominantly mediated by the cytochrome P450 (CYP) 2C19 enzyme. The genetic polymorphism of CYP2C19 significantly impacts the blood concentration of VRZ, particularly the trough concentration (Ctrough), thereby influencing the drug’s efficacy and potentially causing adverse drug reactions (ADRs). Recent research has demonstrated that pharmacogenomics-based VRZ dose adjustments offer more accurate and individualized treatment strategies for individuals with hepatic insufficiency, with the possibility to enhance therapeutic outcomes and reduce ADRs. On the other hand, the security, pharmacokinetics, and dosing of VRZ in individuals with hepatic insufficiency remain unclear, making it challenging to attain optimal Ctrough in individuals with both hepatic insufficiency and IFI, resulting in suboptimal drug efficacy and severe ADRs. Therefore, when using VRZ to treat IFI, drug dosage adjustment based on individuals’ genotypes and hepatic function is necessary. This review summarizes the research progress on the impact of genetic polymorphisms and hepatic insufficiency on VRZ dosage in IFI individuals, compares current international guidelines, elucidates the current application status of VRZ in individuals with hepatic insufficiency, and discusses the influence of CYP2C19, CYP3A4, CYP2C9, and ABCB1 genetic polymorphisms on VRZ dose adjustments and Ctrough at the pharmacogenomic level. Additionally, a comprehensive summary and analysis of existing studies’ recommendations on VRZ dose adjustments based on CYP2C19 genetic polymorphisms and hepatic insufficiency are provided, offering a more comprehensive reference for dose selection and adjustments of VRZ in this patient population.

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Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization

Cited by 4 publications

References 38 publications

Population pharmacokinetics of voriconazole and the role of CYP2C19 genotype on treatment optimization in pediatric patients

Population pharmacokinetics of voriconazole and the role of CYP2C19 genotype on treatment optimization in pediatric patients

Nanotechnology-Based Approaches for Voriconazole Delivery Applied to Invasive Fungal Infections

The impact of gene polymorphism and hepatic insufficiency on voriconazole dose adjustment in invasive fungal infection individuals

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