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A Personalized CYP2C19 Phenotype-Guided Dosing Regimen of Voriconazole Using a Population Pharmacokinetic Analysis

Authors
  • Kim, Yun1
  • Rhee, Su-jin1
  • Park, Wan Beom
  • Yu, Kyung-Sang1
  • Jang, In-Jin1
  • Lee, SeungHwan1
  • 1 (I.-J.J.)
Type
Published Article
Journal
Journal of Clinical Medicine
Publisher
MDPI AG
Publication Date
Feb 10, 2019
Volume
8
Issue
2
Identifiers
DOI: 10.3390/jcm8020227
PMID: 30744151
PMCID: PMC6406770
Source
PubMed Central
Keywords
License
Green

Abstract

Highly variable and non-linear pharmacokinetics of voriconazole are mainly caused by CYP2C19 polymorphisms. This study aimed to develop a mechanistic population pharmacokinetic model including the CYP2C19 phenotype, and to assess the appropriateness of various dosing regimens based on the therapeutic target. A total of 1,828 concentrations from 193 subjects were included in the population pharmacokinetic analysis. A three-compartment model with an inhibition compartment appropriately described the voriconazole pharmacokinetics reflecting auto-inhibition. Voriconazole clearance in the CYP2C19 intermediate metabolizers (IMs) and poor metabolizers (PMs) decreased by 17% and 53% compared to that in the extensive metabolizers (EMs). There was a time-dependent inhibition of clearance to 16.2% of its original value in the CYP2C19 EMs, and the extent of inhibition differed according to the CYP2C19 phenotypes. The proposed CYP2C19 phenotype-guided initial dosing regimens are 400 mg twice daily (bid) for EMs, 200 mg bid for IMs, and 100 mg bid for PMs. This CYP2C19 phenotype-guided initial dosing regimen will provide a rationale for individualizing the optimal voriconazole therapy.

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