Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations

Abstract

f Voriconazole (VCZ) exhibits great inter-and intrapatient variability. The latter variation cannot exclusively be explained by concomitant medications, liver disease or dysfunction, and genetic polymorphisms in cytochrome P450 2C19 (CYP2C19). We hypothesized that inflammatory response in patients under VCZ medication might also influence this fluctuation in concentrations. In this study, we explored the association between inflammation, reflected by the C-reactive protein (CRP) concentration, and VCZ trough concentrations over time. A retrospective analysis of data was performed for patients with more than one steady-state VCZ trough concentration and a CRP concentration measured on the same day. A longitudinal analysis was used for series of observations obtained from many study participants over time. The approach involved inclusion of random effects and autocorrelation in linear models to reflect within-person cross-time correlation. A total of 50 patients were eligible for the study, V oriconazole (VCZ) is the first-line treatment for invasive aspergillosis (1-3). It undergoes extensive hepatic metabolism, principally by cytochrome P450 2C19 (CYP2C19) and to a lesser extent by CYP3A4 and CYP2C9 (4, 5). It is catalyzed into inactive metabolites, with VCZ N-oxide being the principal circulating metabolite (6). The trough concentration of VCZ under steady-state conditions in relation to the MIC is used for practical reasons as the predictive pharmacokinetic/pharmacodynamic parameter (7).VCZ exhibits nonlinear pharmacokinetics in adults with a large inter-and intrapatient variability of drug exposure. These variations might be caused by many factors, including the use of concomitant medications, liver disease or liver dysfunction (1, 3, 5, 8), and, especially, genetic polymorphisms of CYP2C19 (8). However, none of these factors provides a complete explanation of the variability in VCZ concentrations observed in previous studies (9, 10).Data are now emerging that identify a decrease in the capacity of metabolic pathways to handle drugs during infections and diseases that involve an inflammatory response (11)(12)(13)(14). We were the first to associate inflammation, reflected by the C-reactive protein (CRP) concentration, with the VCZ trough concentration (15), as well as finding an association between the CRP concentration and the VCZ N-oxide/VCZ ratio (16), identifying a possible explanation for some of the variability in VCZ concentrations.Previously, the relationship between CRP and the VCZ trough concentration was evaluated at a single point in time (15). However, the inflammatory response represents a coordinated set of physiological events, while the metabolic and inflammatory status of each patient is different and may vary over time during VCZ treatment. Therefore, to detect changes in VCZ trough concentrations of the patients at both the group and the individual levels, the studies should be extended beyond a single moment in time in order to explore all sequences of events.To further explore the intrap...

Voriconazole hepatotoxicity as a result of steroid withdrawal in a patient with allergic bronchopulmonary aspergillosis

“…Nevertheless, we need further studies investigating the effect of corticosteroid dosing on voriconazole metabolism as well as the effect of different glucocorticoids. In addition, the effect on voriconazole concentration caused by prednisone in the present case was higher to the observed in previous studies (a 5.60‐fold increase in voriconazole concentration when prednisone was discontinued); therefore, other causes may have contributed to decrease the elimination of the drug from the blood such as the inflammatory state of the patient .…”

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

“…The possible relationship between upregulation of VCZ and specific proinflammatory markers had not yet been described. Recently, a study with a comparable design and patient group was published, using another linear mixed model to determine the association of CRP with VCZ concentrations . We used a different type of linear mixed model because of the skewness of our data, which made log‐transformation essential.…”

“…The Gaussian serial covariance structure in combination with a random intercept takes into account the fact that observations within a patient decrease if the time between observations increases. This resulted in lower values of AIC compared with using other approaches . The lower values of the AIC indicate a better fit of our data in this model.…”

“…CRP is produced by hepatocytes, predominantly under the transcriptional control of interleukin (IL) 6 . Recently, a significant correlation between CRP and VCZ trough concentrations was reported . As in vitro studies have demonstrated that IL‐6 and other upstream proinflammatory cytokines downregulate CYP2C19 and CYP3A4 gene expression , downregulation of these CYP enzymes by elevated concentrations of IL‐6 might cause an increase in VCZ trough concentrations.…”

The effect of inflammation on voriconazole trough concentrations in children

“…Recently, in adults, it was shown that severe inflammation, reflected by C‐reactive protein (CRP) value, was associated with elevated voriconazole trough concentrations . This was explained by inflammatory stimuli leading to downregulation of CYP isoenzymes, resulting in reduced metabolism of voriconazole .…”