Voriconazole therapeutic drug monitoring: focus on safety

Pasqualotto, Alessandro C.; Xavier, Melissa Orzechowski; Andreolla, Huander Felipe; Linden, Rafael

doi:10.1517/14740330903485637

Cited by 61 publications

(61 citation statements)

References 60 publications

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“…Second, in this study no evaluation of genetic variations for the hepatic CYP isoenzymes was available. As genetic variants of CYP2C19 alter the concentration of VCZ (29,30), further studies including CYP2C19 genotypes would contribute to clarifying our results. Nonetheless, it is unlikely that CYP2C19 polymorphisms completely explain the variability of VCZ pharmacokinetics due to a low incidence among Caucasians, who made up the vast majority of our study population (31).…”

Section: Discussionmentioning

confidence: 88%

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: Discussionmentioning

confidence: 88%

Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations

Ventura

Wanrooy

Span

et al. 2016

Antimicrob Agents Chemother

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“…Voriconazole is the recommended drug for the primary therapy of invasive aspergillosis (35). Another azole drug, posaconazole, is used prophylactically, as it has been reported to reduce the number of invasive fungal infections in neutropenic patients (48).…”

Section: Discussionmentioning

confidence: 99%

Role of Aspergillus lentulus 14-α Sterol Demethylase (Cyp51A) in Azole Drug Susceptibility

Mellado

Alcàzar-Fuoli

Cuenca‐Estrella

et al. 2011

Antimicrob Agents Chemother

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Recent studies have demonstrated that some morphologically atypical Aspergillus fumigatus strains are different species belonging to the section Fumigati. Aspergillus lentulus, one of these sibling species, is increasingly reported in patients under corticosteroid treatment. MICs of most antifungals in clinical use are elevated against A. lentulus, and it shows primary resistance to azole drugs. Two A. lentulus cytochrome P450 14-␣ sterol demethylases, encoded by A. lentulus cyp51A (Alcyp51A) and Alcyp51B genes, were identified. Targeted cyp51A gene knockout in A. lentulus showed that the intrinsic azole resistance of this species is cyp51A dependent. The ⌬cyp51A strain was morphologically indistinguishable from the A. lentulus wild-type strain, retaining the ability to cause pulmonary disease in neutropenic mice. The heterologous expression of A. lentulus cyp51A was performed in an A. fumigatus cyp51A-deficient strain, confirming that Cyp51A is responsible for the differences in A. lentulus-azole drug interaction.

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“…Steady-state plasma concentrations are attained after 5-7 days of treatment. Comprising a narrow therapeutic index, pharmacokinetics of Vrc is profoundly influenced by food and drug interactions and inter-individual variability regardless of route of administration [8][9][10][11]. Factors well documented to be associated with interindividual variability of voriconazole exposure include liver dysfunction, gastrointestinal abnormalities (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…Factors well documented to be associated with interindividual variability of voriconazole exposure include liver dysfunction, gastrointestinal abnormalities (e.g. mucositis or diarrhea) impairing drug absorption, intake with or without food, alcohol abuse in the past, concomitant use of potent CYP450 inducers or inhibitors, CYP2C19 genetic polymorphism; thus rationalizing the necessity for therapeutic drug monitoring (TDM) of voriconazole [6][7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Plasma Voriconazole Estimation by HPLC

2015

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Voriconazole, an antifungal drug exhibiting wide inter-individual variability, is an ideal candidate for therapeutic drug monitoring (TDM). The aim of the present study was to standardize a simple, sensitive and rapid high performance liquid chromatography (HPLC) method with ultraviolet detection to determine plasma voriconazole concentration. The HPLC method consisted of a combination of acetonitrile and water (7:3) as mobile phase with 1 ml/min flow rate and detection at 255 nm. Plasma protein precipitation was carried out using perchloric acid and the filtered supernatant was passed through C18 column (250 9 4.6 mm, 5 lm) for the separation of voriconazole. The limit of quantification of voriconazole was 0.2 mg/L. The assay was validated with a linearity of 0.2-15 mg/L and used clinically for TDM in patient samples. The interassay precision was below 15 % for routine quality control samples. Weight based voriconazole doses were prescribed to 26 patients for empirical treatment of invasive fungal infections. Voriconazole therapy was managed from the baseline drug levels and follow up analysis reflected achievement in clinical efficacy. Routine TDM of voriconazole may reduce adverse events and improve the treatment response in invasive fungal infections.

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Voriconazole therapeutic drug monitoring: focus on safety

Abstract: Therapy with voriconazole may be better guided by measuring voriconazole concentrations in the plasma.

Cited by 61 publications

References 60 publications

Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations

Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations

Role of Aspergillus lentulus 14-α Sterol Demethylase (Cyp51A) in Azole Drug Susceptibility

Plasma Voriconazole Estimation by HPLC

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