Pharmacogenetics may Influence the Impact of Inflammation on Voriconazole Trough Concentrations

Abstract

How pharmacogenetics modulates the inhibitory effects of inflammation on voriconazole trough concentration (Cmin) remains unknown. In 29 recipients of allogeneic hematopoietic stem cell transplantation retrospectively studied, both a genetic score (which aggregated CYP2C19 and CYP3A genotypes) and inflammation significantly influenced voriconazole Cmin (n = 260). A trend toward (p = 0.03) a greater impact of inflammation in patients with the highest genetic score (corresponding to ultra-rapid metabolizers) was observed. Further researches are needed to confirm these data.

Inflammation is a potential risk factor of voriconazole overdose in hematological patients

“…Such an elevated CRP level associated risk of VRC overdose is in accordance with several previous studies reporting positive associations between elevated CRP levels and high VRC C min . This is probably related to inflammation‐induced phenoconversion, during which proinflammatory cytokines, such as interleukin‐6, reduce both CYP3A4 and CYP2C19 expression and activity .…”

“…These data suggest that hematological patients may be at increased risk of supratherapeutic VRC C min and associated toxicity when they exhibit increased CRP levels, which is very frequent for patients with IA [24,25]. Such an elevated CRP level associated risk of VRC overdose is in accordance with several previous studies reporting positive associations between elevated CRP levels and high VRC C min [15,16,[26][27][28][29]. This is probably related to inflammation-induced phenoconversion, during which proinflammatory cytokines, such as interleukin-6, reduce both CYP3A4 and CYP2C19 expression and activity [30].…”

Inflammation is the main risk factor of voriconazole overdose in hematological patients

“…Such an elevated CRP-level associated risk of VRC overdose is in accordance with several previous studies reporting positive associations between elevated CRP levels and high VRC Cmin (15, 16, 26–28). This is probably related to inflammation-induced phenoconversion, during which proinflammatory cytokines, such as interleukin-6, reduce both CYP3A4 and CYP2C19 expression and activity (29).…”

“…Although subtherapeutic VRC Cmin are often explained by gain-of-function single nucleotide polymorphism (SNP) *17 for CYP2C19 (at least in the Caucasian population) (8–11), comedication by enzymatic inducers (12), or non-observance (9), the determinants of supratherapeutic VRC Cmin have been less investigated. Numerous factors, such as liver dysfunction, the use of enzymatic inhibitors (13), the presence of loss-of-function SNPs for CYP2C19 (14), and inflammation (15, 16), have already been identified to be associated with increased VRC Cmin, but their impact on the occurrence of VRC overdose has never been investigated. This issue is all the more relevant as 1) the magnitude of the effect of each individual factor on VRC Cmin appears to be relatively weak (4) and 2) some of these factors, such as inflammation and genetic variants of CYP2C19, may be linked (17–19) and interact (15, 16).…”

“…Numerous factors, such as liver dysfunction, the use of enzymatic inhibitors (13), the presence of loss-of-function SNPs for CYP2C19 (14), and inflammation (15, 16), have already been identified to be associated with increased VRC Cmin, but their impact on the occurrence of VRC overdose has never been investigated. This issue is all the more relevant as 1) the magnitude of the effect of each individual factor on VRC Cmin appears to be relatively weak (4) and 2) some of these factors, such as inflammation and genetic variants of CYP2C19, may be linked (17–19) and interact (15, 16). Here, we aimed to identify risk factors associated with VRC overdose in a cohort of hematological patients treated by VRC followed by TDM.…”