Influence of Inflammation on Voriconazole Metabolism

Ventura, Miguel; Span, L. F. R.; Heuvel, Edwin R. van den; Groothuis, Geny M. M.; Alffenaar, Jan‐Willem C.

doi:10.1128/aac.04789-14

Cited by 43 publications

(46 citation statements)

References 12 publications

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“…In conclusion, based on the results of our longitudinal analysis and as corroborated by our previous studies (15,16), these findings may provide estimates of the inflammatory response as a source of variability of VCZ concentrations. The inflammatory response plays a role in the largely unpredictable pharmacokinetics of VCZ, especially in patients with a higher and/or variable inflammatory status.…”

Section: Discussionsupporting

confidence: 72%

“…In previous studies, we have observed that an inflammatory state raised the concentration of VCZ in terms of its metabolic reduction (16). It has been determined that for every 1-mg/liter increase in the CRP concentration, the VCZ trough concentration was 0.015 mg/liter higher (15), and as the longitudinal estimate (0.014) is very close to this value, this suggests that it is stable over time.…”

Section: Discussionmentioning

confidence: 61%

“…Additionally, the metabolic ratio, defined as VCZ N-oxide/ VCZ, decreased by 0.010 for every unit increase in the CRP concentration (16). We therefore hypothesized that inflammation induces downregulation of CYP2C19 in patients treated with VCZ (15,16), suggesting that elevated amounts of inflammatory cytokines influence the CYP isoenzymes and thus change the rate of metabolism of VCZ, resulting in increased drug concentrations (15,16).…”

Section: Discussionmentioning

confidence: 99%

“…We therefore hypothesized that inflammation induces downregulation of CYP2C19 in patients treated with VCZ (15,16), suggesting that elevated amounts of inflammatory cytokines influence the CYP isoenzymes and thus change the rate of metabolism of VCZ, resulting in increased drug concentrations (15,16). For example, an increase in the CRP concentration from 11 mg/liter to 196 mg/liter is likely to result in an increase in the VCZ concentration from 2.7 mg/liter to approximately 5.3 mg/ liter.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations

Ventura

Wanrooy

Span

et al. 2016

Antimicrob Agents Chemother

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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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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations

Ventura

Wanrooy

Span

et al. 2016

Antimicrob Agents Chemother

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Metabolism‐Based Drug–Drug Interactions in Critically Ill Patients: Clinical Relevance and Predictability ofIn VitroSystems

Mouly

Spriet

Wauters

et al. 2016

Encyclopedia of Drug Metabolism and Interactions

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Drug–drug interactions (DDIs) contribute mainly to the incidence of adverse drug reactions. Important advances in the knowledge of human drug‐metabolizing enzymes have fueled the integration of in vitro drug metabolism and clinical DDI studies for the use in drug development programs and in the clinical setting. The activities of cytochrome P450 (CYP) 3A4 and P‐glycoprotein are critical determinants of drug clearance and are involved in the mechanism of numerous clinically relevant DDI. Human liver, intestinal samples, and recombinant human CYP3A4 are now available as in vitro screening tools to predict the potential for in vivo DDI. The interpretation and extrapolation of in vitro interaction data to in vivo situations require a good understanding of pharmacokinetic principles. In this chapter, research on drug metabolism and DDI along with examples illustrating the utility of specific in vitro or in vivo approaches is presented. In addition, the impact and clinical relevance of complexities such as dosing‐route‐dependent effects, multisite kinetics of drug‐metabolizing enzymes, and non‐CYP determinants of metabolic clearance are addressed.

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Modulation of CYP450 Activities in Patients With Type 2 Diabetes

Gravel

Chiasson

Turgeon

et al. 2019

Clin Pharma and Therapeutics

101

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We conducted a comprehensive in vivo study evaluating the influence of type 2 diabetes (T2D) on major cytochrome P450 (CYP450) activities. These activities were assessed in 38 T2D and 35 non-T2D subjects after a single oral administration of a cocktail of probe drugs: 100 mg caffeine (CYP1A2), 100 mg bupropion (CYP2B6), 250 mg tolbutamide (CYP2C9), 20 mg omeprazole (CYP2C19), 30 mg dextromethorphan (CYP2D6), 2 mg midazolam (CYP3As), and 250 mg chlorzoxazone (alone; CYP2E1). Mean metabolic activity for CYP2C19, CYP2B6, and CYP3A was decreased in subjects with T2D by about 46%, 45%, and 38% (P < 0.01), respectively. CYP1A2 and CYP2C9 activities seemed slightly increased in subjects with diabetes, and no difference was observed for CYP2D6 or CYP2E1 activities. Several covariables, such as inflammatory markers (interleukin (IL)-1ß, IL-6, gamma interferon, and tumor necrosis factor alpha), genotypes, and diabetes-related and demographic-related factors were considered in our analyses. Our results indicate that low chronic inflammatory status associated with T2D modulates CYP450 activities in an isoform-specific manner.

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Influence of Inflammation on Voriconazole Metabolism

Cited by 43 publications

References 12 publications

Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations

Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations

Metabolism‐Based Drug–Drug Interactions in Critically Ill Patients: Clinical Relevance and Predictability ofIn VitroSystems

Modulation of CYP450 Activities in Patients With Type 2 Diabetes

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