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J. Clin. Med. 2019, 8(2), 227; https://doi.org/10.3390/jcm8020227

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

1
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Korea
2
Department of Internal Medicine, Seoul National University College of Medicine and Hospital, Seoul 03080, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to the manuscript.
Received: 16 January 2019 / Revised: 28 January 2019 / Accepted: 31 January 2019 / Published: 10 February 2019
(This article belongs to the Special Issue Advances in Antibacterial Drug Discovery and Therapy)
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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. View Full-Text
Keywords: antifungal agent; population pharmacokinetics; pharmacogenetics; infectious disease; individualization antifungal agent; population pharmacokinetics; pharmacogenetics; infectious disease; individualization
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Kim, Y.; Rhee, S.-J.; Park, W.B.; Yu, K.-S.; Jang, I.-J.; Lee, S. A Personalized CYP2C19 Phenotype-Guided Dosing Regimen of Voriconazole Using a Population Pharmacokinetic Analysis. J. Clin. Med. 2019, 8, 227.

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