Vol.67 No.4 July 2019

Pharmacokinetic approach towards some issues related to voriconazole dosage based on the TDM guideline

Mao Hagihara^{1, 2)}, Hideo Kato³⁾, Yuki Yokoyama³⁾, Arufumi Shiota^{3, 4)}, Yuichi Shibata³⁾, Hiroki Watanabe^{2, 4)}, Nobuhiro Asai^{2, 4)}, Yusuke Koizumi^{2, 4)}, Yuka Yamagishi^{2, 4)} and Hiroshige Mikamo^{2, 4)}

¹⁾Department of Molecular Epidemiology and Biomedical Sciences, Aichi Medical University, 1-1 Yazako Karimata, Nagakute, Aichi, Japan
²⁾Department of Clinical Infectious Diseases, Aichi Medical University
³⁾Department of Pharmacy, Aichi Medical University Hospital
⁴⁾Department of Infection Control and Prevention, Aichi Medical University Hospital

Abstract

Voriconazole (VRCZ), a triazole antifungal agent, has been demonstrated to show efficacy against fungal infections. This antifungal agent is known to exhibit highly variable non-linear pharmacokinetics, and its extreme intra- and interpatient variability in plasma concentrations in the context of established exposure-response/toxicity relationships has triggered the need for therapeutic drug monitoring (TDM) in daily practice. In the Japanese antibiotics TDM guideline 2016, some experts recommend that the VRCZ blood trough concentration be maintained at ≥1-2 μg/mL for efficacy and at ≤4-5 μg/mL for safety. However, the optimal therapeutic range for specific populations, such as patients with severe infections, remains under debate. Also, VRCZ is metabolized in the liver, primarily through cytochrome CYP2C19, and to a lesser extent, through CYP3A4 and CYP2C9. Therefore, setting an adequate dosing regimen for VRCZ remains challenging, especially in patients suspected as being CYP2C19 poor metabolizers. As VRCZ has the potential to produce adverse reactions such as hepatotoxicity, neurotoxicity (hallucinations) and visual disturbances, TDM is necessary to optimize treatment. However, domestic data on the relationship of the VRCZ blood concentrations to the risk of neurotoxicity and visual disturbances are scarce. Such evaluations can provide useful information for adjusting the drug dosage to improve the clinical safety and effectiveness of VRCZ treatment. The objective of this review was to assess these issues from the standpoint of pharmacokinetic approaches based on our data and previously published data.

Key word

voriconazole, population pharmacokinetics, therapeutic drug monitoring (TDM)

Received

October 29, 2018

Accepted

January 29, 2019

Jpn. J. Chemother. 67 (4): 457-465, 2019