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. 2021 May 13;10(10):2089.
doi: 10.3390/jcm10102089.

Combined Impact of Inflammation and Pharmacogenomic Variants on Voriconazole Trough Concentrations: A Meta-Analysis of Individual Data

Léa Bolcato  1 , Charles Khouri  2 , Anette Veringa  3 , Jan Willem C Alffenaar  3   4   5   6 , Takahiro Yamada  7 , Takafumi Naito  7 , Fabien Lamoureux  8 , Xavier Fonrose  1 , Françoise Stanke-Labesque  1   9 , Elodie Gautier-Veyret  1   9
Affiliations

Combined Impact of Inflammation and Pharmacogenomic Variants on Voriconazole Trough Concentrations: A Meta-Analysis of Individual Data

Léa Bolcato et al. J Clin Med. .

Abstract

Few studies have simultaneously investigated the impact of inflammation and genetic polymorphisms of cytochromes P450 2C19 and 3A4 on voriconazole trough concentrations. We aimed to define the respective impact of inflammation and genetic polymorphisms on voriconazole exposure by performing individual data meta-analyses. A systematic literature review was conducted using PubMed to identify studies focusing on voriconazole therapeutic drug monitoring with data of both inflammation (assessed by C-reactive protein level) and the pharmacogenomics of cytochromes P450. Individual patient data were collected and analyzed in a mixed-effect model. In total, 203 patients and 754 voriconazole trough concentrations from six studies were included. Voriconazole trough concentrations were independently influenced by age, dose, C-reactive protein level, and both cytochrome P450 2C19 and 3A4 genotype, considered individually or through a combined genetic score. An increase in the C-reactive protein of 10, 50, or 100 mg/L was associated with an increased voriconazole trough concentration of 6, 35, or 82%, respectively. The inhibitory effect of inflammation appeared to be less important for patients with loss-of-function polymorphisms for cytochrome P450 2C19. Voriconazole exposure is influenced by age, inflammatory status, and the genotypes of both cytochromes P450 2C19 and 3A4, suggesting that all these determinants need to be considered in approaches of personalization of voriconazole treatment.

Keywords: inflammation; personalized treatment; pharmacogenomics; therapeutic drug monitoring; voriconazole.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flow diagram of study selection.
Figure 2
Figure 2
Effects of an increase in CRP levels on the voriconazole (VRC) trough concentration (Cmin) according to the CYP2C19 phenotype. The figure illustrates the predicted increase in VRC Cmin as a function of CRP level from mixed-effects model 2. The blue, green, and red curves represent patients with decreased CYP2C19 metabolic capacity (intermediate (IM) and poor metabolizers (PM)), those with increased metabolic capacity (rapid (RM) and ultrarapid metabolizers (UM)), and those with extensive metabolic capacity (extensive metabolizers (EM)), respectively. Cmin: trough concentration; CRP: C-reactive protein; VRC: voriconazole; CYP: cytochrome P450; EM: extensive metabolizer; IM: intermediate metabolizer; PM: poor metabolizer; RM: rapid metabolizer; UM: ultrarapid metabolizer.
See this image and copyright information in PMC

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