Impact of polymorphisms of pharmacokinetics‐related genes and the inflammatory response on the metabolism of voriconazole

Abstract

The effects of inflammatory responses and polymorphisms of the genes encoding cytochrome P450 (CYP) ( CYP2C19 and CYP3A5 ), flavin‐containing monooxygenase 3 ( FMO3 ), pregnane X receptor ( NR1I2 ), constitutive androstane receptor ( NR1I3 ), and CYP oxidoreductase ( POR ) on the ratio of voriconazole (VRCZ) N ‐oxide to VRCZ (VNO/VRCZ) and steady‐state trough concentrations (C 0h ) of VRCZ were investigated. A total of 56 blood samples were collected from 36 Japanese patients. Results of multiple linear regression analyses demonstrated that the presence of the extensive metabolizer CYP2C19 genotype, the dose per administration, and the presence of the NR1I2 rs3814057 C/C genotype were independent factors influencing the VNO/VRCZ ratio in patients with CRP levels of less than 40 mg/L (standardized regression coefficients (SRC) = 0.448, −0.301, and 0.390, respectively; all p < .05). With regard to the concentration of VRCZ itself, in addition to the above factors, the presence of the NR1I2 rs7643645 G/G and rs3814055 T/T genotypes were found to be independent factors influencing the VRCZ C 0h in these patients (SRC = −0.430, 0.424, −0.326, 0.406 and −0.455, respectively; all p < .05). On the contrary, in patients with CRP levels of at least 40 mg/L, no independent factors were found to affect VNO/VRCZ and VRCZ C 0h . Inflammatory responses, and CYP2C19 and NR1I2 polymorphisms may be useful information for the individualization of VRCZ dosages.

Impact of Inflammation on Intra-individual Variation in Trough Voriconazole Concentration in Patients with Hematological Malignancies

“…NR1/2 encodes nuclear receptors leading to the induction of multiple genes that encode metabolic enzymes including CYP. 29) The effect of NR1/2 polymorphisms on VRCZ metabolism was not examined in this study. Further, the calculation periods of Δ ranged widely from 1 to 53 d. Thus, the patient background at the two time points for calculating Δ may have changed in some patients.…”

Individualized treatment with voriconazole in the Chinese population: Inflammation level as a novel marker for dose optimization

“…This study was conducted in part in a real-life clinical setting; patients were stratified according to the CRP level (CRP < 40 mg/L; CRP ≥ 40 mg/L) to explore the influence of CYP2C19 polymorphisms combined with the inflammatory status on the VRC metabolism. Additionally, the contributions of multiple single nucleotide polymorphisms (SNPs) (CYP2C9, CYP3A4, CYP3A5, FMO3, [27][28][29] ABCB1, 30,31 NR1I2, NR1I3 and POR [32][33][34] ) and non-genetic factors such as age, body mass index (BMI), weight, sex, liver function, kidney function and concomitant medication to VRC C min ss were also discussed. 33,[35][36][37] Another part of the study was conducted in rats, where we further explored the effect of inflammatory status on the pharmacokinetics of VRC and its potential mechanism by single intragastric administration of VRC in the inflammatory group (LPS 5 mg/kg) and the control group.…”

Dosage optimization of voriconazole in children with haematological malignancies based on population pharmacokinetics

“…However, there is great inter‐individual variability in voriconazole plasma concentration, which brings great challenges to the clinic. Multiple factors such as non‐linear pharmacokinetics, gender, age, liver function, pharmacogenetic polymorphisms, drug interactions, and inflammation status have been reported to contribute to this variability 6–11 . Notably, this characteristic is more obvious in children than in adults, 12,13 which makes it difficult to achieve a therapeutic window for voriconazole in children and further contributes to treatment failure or increases the risk of adverse outcomes 14 …”

“…Multiple factors such as non-linear pharmacokinetics, gender, age, liver function, pharmacogenetic polymorphisms, drug interactions, and inflammation status have been reported to contribute to this variability. [6][7][8][9][10][11] Notably, this characteristic is more obvious in children than in adults, 12,13 which makes it difficult to achieve a therapeutic window for voriconazole in children and further contributes to treatment failure or increases the risk of adverse outcomes. 14 Population pharmacokinetics (PPK) analysis can assess the basic characteristics of pharmacokinetics and identify the origins of interand intra-individual variability, 15 which could help predict individualized dosages and keep drug exposure to the desired level.…”