f Voriconazole concentrations display a large variability, which cannot completely be explained by known factors. Inflammation may be a contributing factor, as inflammatory stimuli can change the activities and expression levels of cytochrome P450 isoenzymes. We explored the correlation between inflammation, reflected by C-reactive protein (

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...

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Posaconazole exposure is insufficient in more than 40% of patients at risk of or with invasive fungal disease, and posaconazole exposure is positively correlated with a successful treatment outcome. Therapeutic drug monitoring of posaconazole can detect underexposure and can be helpful in treatment optimization.

The method developed has a straightforward sample preparation and uses a structural analog as the internal standard. This method has been applied successfully for the measurement of anidulafungin and caspofungin concentrations in patient samples, both for clinical practice and for research.

e Efficacy of anidulafungin is driven by the area under the concentration-time curve (AUC)/MIC ratio. Determination of the anidulafungin AUC along with MIC values can therefore be useful. Since obtaining a full concentration-time curve to determine an AUC is not always feasible or appropriate, limited-sampling strategies may be useful in adequately estimating exposure. The objective of this study was to develop a model to predict the individual anidulafungin exposure in critically ill patients using limited-sampling strategies. Pharmacokinetic data were derived from 20 critically ill patients with invasive candidiasis treated with anidulafungin. These data were used to develop a two-compartment model in MW‫گ‬Pharm using an iterative 2-stage Bayesian procedure. Limited-sampling strategies were subsequently investigated using two methods, a Bayesian analysis and a linear regression analysis. The best possible strategies for these two methods were evaluated by a Bland-Altman analysis for correlation of the predicted and observed AUC from 0 to 24 h (AUC 0 -24 ) values. Anidulafungin exposure can be adequately estimated with the concentration from a single sample drawn 12 h after the start of the infusion either by linear regression (R 2 ‫؍‬ 0.99; bias, 0.05%; root mean square error [RMSE], 3%) or using a population pharmacokinetic model (R 2 ‫؍‬ 0.89; bias, ؊0.1%; RMSE, 9%) in critically ill patients and also in less severely ill patients, as reflected by healthy volunteers. Limited sampling can be advantageous for future studies evaluating the pharmacokinetics and pharmacodynamics of anidulafungin and for therapeutic drug monitoring in selected patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01047267.)

The performance of voriconazole therapeutic drug monitoring can still be improved although voriconazole concentrations were monitored in most patients. A multidisciplinary approach-for instance by means of antifungal stewardship-will probably be able to overcome problems encountered such as timing of sampling, incompleteness of data in clinical context, and lack of implementation of recommendations.