Moderate correlation between systemic IL‐6 responses and CRP with trough concentrations of voriconazole

Abstract

AimsVoriconazole (VCZ) exhibits wide intrapatient pharmacokinetic variability, which is disadvantageous because of its narrow therapeutic range. A considerable part of this variation remains unexplainable, despite extensive knowledge of this drug. It is hypothesized that inflammation has an impact on VCZ pharmacokinetics. In the present study, we investigated the correlation between VCZ trough concentrations and various cytokines.MethodsA prospective single‐centre analysis was performed in adult haematology patients receiving VCZ for possible, probable or proven invasive fungal disease. A linear mixed model was built to explore the contribution of each of the seven pro‐ and anti‐inflammatory cytokines to VCZ trough levels. The Akaike information criterion (AIC) was used to determine the model that fitted the best.ResultsTwenty‐two patients, with a total of 143 combined samples of VCZ trough levels and cytokines, were included. A significant correlation (P < 0.005) was found between VCZ trough concentrations and interleukin (IL) 6, IL‐8 and C‐reactive protein (CRP). IL‐6 showed the lowest AIC, although differences with the other mediators were marginal.ConclusionVCZ trough concentrations correlate with IL‐6, IL‐8 and CRP levels but only moderately explain the variability in VCZ pharmacokinetics. Future prospective studies should be undertaken to confirm these findings, and incorporate the data obtained into pharmacokinetic models, to refine the predictive behaviour.

The Influence of Proinflammatory Cytokines on Voriconazole Trough Concentration in Patients With Different Forms of Hematologic Disorders

“…27 Our findings showed that the increase in VCZ-C min was significantly associated with a decrease in IL-6 concentration. However, our findings differed from previous clinical study 38 whereby a positive relationship between IL-6 and VCZ-C min was observed. The clear reason for this discrepancy could not be elucidated.…”

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].…”

Voriconazole: A Review of Population Pharmacokinetic Analyses

“…Thus, other potential covariates should be tested in model building in future studies. In recent years, numerous studies have reported that inflammation, which can be reflected by the C-reactive protein levels, might influence the voriconazole trough concentration [52][53][54][55][56][57][58]. A retrospective study revealed that despite similar voriconazole doses, the trough concentrations of voriconazole in patients with severe inflammation are significantly higher than those in patients with zero to moderate inflammation.…”