Patients in earlier phases of the cardiomyopathy, with a less altered ventricular geometry, seem to have a greater probability of becoming super-responders.

dVoriconazole pharmacokinetics shows a large inter-and intrapatient variability. Inflammation is associated with changes in the expression of CYP isoenzymes. Here, we evaluated the influence of inflammation, marked by C-reactive protein (CRP) levels in blood, on the metabolism of voriconazole. Observational data showed an association between CRP level and the ratio of voriconazole N-oxide to voriconazole. V oriconazole (VCZ) is recommended as a first-line treatment for invasive aspergillosis (1). It undergoes extensive hepatic metabolism, primarily by CYP2C19 and to a lesser extent by CYP3A4 and CYP2C9. Besides polymorphism as a predominant factor generating highly variable interpatient pharmacokinetics of VCZ, drug-drug interactions and liver function may also influence VCZ exposure (2-4). A recent observation of high VCZ concentrations during severe inflammation (5) could explain a part of the previously observed large intrapatient variability (6). This effect was explained by a downregulation of drug-metabolizing enzymes caused by inflammation (7,8).To further elucidate this clinical observation, it was relevant to evaluate the metabolic rate of VCZ during periods of severe inflammation. The metabolic rate of VCZ was expressed as the ratio of N-oxide VCZ to VCZ (metabolic ratio [MR]). In this study, we hypothesize that the N-oxide VCZ/VCZ ratio would be decreased during severe inflammation (defined by C-reactive protein [CRP] levels of Ͼ100 mg/ml), possibly due to a decrease in the metabolic function of CYP2C19.In this study, performed in the University Medical Centre Groningen, the Netherlands, medical data from patients who received intravenous or oral VCZ for treatment or prophylaxis between December 2012 and July 2013 and were subjected to therapeutic-drug monitoring (TDM) and monitoring of CRP were retrospectively analyzed. All patients aged at least 18 years who received VCZ were considered eligible for the study if they had at least 3 data sets of N-oxide VCZ/VCZ concentration ratios and corresponding CRP levels determined on the same day. This study, being of a retrospective nature, was evaluated by the local ethics committee (IRB 2013-491) and was approved according to Dutch law.Patients were excluded if a strong cytochrome P450 inducer or inhibitor affecting VCZ metabolism was coadministered (4) or if the mean value of liver function tests exceeded 5 times the upper level of normal. The liver functions evaluated were alanine aminotransferase (ALT; normal value, Ͻ45 U/liter), aspartate aminotransferase (AST; normal value, Ͻ40 U/liter), alkaline phosphatase (AP; normal value, Ͻ120 U/liter), and bilirubin (normal value, 5.1 to 32.5 mol/liter). VCZ and N-oxide VCZ concentrations were measured with a validated and verified assay (9, 10). CRP was measured by a turbidimetric assay (Roche Modular; Roche, Mannheim, Germany).In the study, data for a total of 77 patients who were subjected to routine TDM during the period from December 2012 to July 2013 were evaluated. After the evaluation, 28 patients were el...

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...