Multicenter Study of Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring

Dolton, Michael; Ray, John E.; Chen, Sharon C.-A.; Ng, Kingsley; Pont, Lisa G.; McLachlan, Andrew J.

doi:10.1128/aac.00626-12

Cited by 240 publications

(294 citation statements)

References 33 publications

Supporting

Mentioning

266

Contrasting

Unclassified

Order By: Relevance

“…TDM is used to avoid treatment failure, resistance, or toxicity. The optimal plasma trough levels (with HPLC/MS) are 1-4 mg/L for itraconazole, 2-6 mg/L for voriconazole, and greater than 1 mg/L for posaconazole suspension [60][61][62]. The newer tablet or intravenous formulation of posacoanzole is more likely to achieve target plasma levels but there is limited evidence for routine TDM.…”

Section: Invasive Aspergillosismentioning

confidence: 99%

Intensive care medicine research agenda on invasive fungal infection in critically ill patients

et al. 2017

View full text Add to dashboard Cite

Purpose:To describe concisely the current standards of care, major recent advances, common beliefs that have been contradicted by recent trials, areas of uncertainty, and clinical studies that need to be performed over the next decade and their expected outcomes with regard to Candida and Aspergillus infections in non-neutropenic patients in the ICU setting. Methods:A systematic review of the medical literature taking account of national and international guidelines and expert opinion. Results:Severe invasive fungal infections (IFIs) are becoming increasingly frequent in critically ill patients. Approximately 80% of IFIs are due to Candida spp. and 0.3-19% to Aspergillus spp. Recent observations emphasize the necessity of building a worldwide sentinel network to monitor the emergence of new fungal species and changes in susceptibility. Robust data on the attributable mortality are essential for the design of clinical studies with mortality endpoints. Although early antifungal therapy for Candida has been recommended in patients with risk factors, sepsis of unknown cause, and positive Candida serum biomarkers [β-1 → 3-d-glucan (BDG) and Candida albicans germ tube antibody (CAGTA)], its usefulness and influence on outcome need to be confirmed. Future studies may specifically address the optimal diagnostic and therapeutic strategies for patients with abdominal candidiasis. Better knowledge of the pharmacokinetics of antifungal molecules and tissue penetration is a key issue for intensivists. Regarding invasive aspergillosis, further investigation is needed to determine its incidence in the ICU, its relationship with influenza outbreaks, the clinical impact of rapid diagnosis, and the significance of combination treatment. Conclusions:Fundamental questions regarding IFI have to be addressed over the next decade. The clinical studies described in this research agenda should provide a template and set priorities for the clinical investigations that need to be performed.

show abstract

Section: Invasive Aspergillosismentioning

confidence: 99%

Intensive care medicine research agenda on invasive fungal infection in critically ill patients

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Two out of six TDM patients with concentrations of Ͻ2 mg/liter were nonresponders (16). Meanwhile, in a multicenter study of voriconazole PK and TDM involving 201 patients, 26% of patients with concentrations of Ͻ1.7 mg/liter failed treatment while only 7% of patients with concentrations of Ͼ1.7 mg/liter were nonresponders (14). Comparable serum concentrations for treatment failure were found in a study by Pascual et al, where patients with concentrations of Ͻ1.5 mg/liter had Ͻ85% probability of response (11).…”

Section: Fig 1 Histogram Of Daily Voriconazole Doses Administeredmentioning

confidence: 99%

“…Subtherapeutic concentrations have been linked to higher failure rates in patients with life-threatening invasive fungal infections, and supratherapeutic concentrations are associated with neurological and hepatic toxicity (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Voriconazole is primarily metabolized by CYP2C19, which commonly exhibits genetic polymorphism, leading to variable PK and leaving certain populations susceptible to decreased metabolism and increased plasma concentrations of voriconazole (20)(21)(22)(23).…”

mentioning

confidence: 99%

Comparative Evaluation of the Predictive Performances of Three Different Structural Population Pharmacokinetic Models To Predict Future Voriconazole Concentrations

Farkas

Daróczi²,

Villasurda

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

i Bayesian methods for voriconazole therapeutic drug monitoring (TDM) have been reported previously, but there are only sparse reports comparing the accuracy and precision of predictions of published models. Furthermore, the comparative accuracy of linear, mixed linear and nonlinear, or entirely nonlinear models may be of high clinical relevance. In this study, models were coded into individually designed optimum dosing strategies (ID-ODS) with voriconazole concentration data analyzed using inverse Bayesian modeling. The data used were from two independent data sets, patients with proven or suspected invasive fungal infections (n ‫؍‬ 57) and hematopoietic stem cell transplant recipients (n ‫؍‬ 10). Observed voriconazole concentrations were predicted whereby for each concentration value, the data available to that point were used to predict that value. The mean prediction error (ME) and mean squared prediction error (MSE) and their 95% confidence intervals (95% CI) were calculated to measure absolute bias and precision, while ⌬ME and ⌬MSE and their 95% CI were used to measure relative bias and precision, respectively. A total of 519 voriconazole concentrations were analyzed using three models. Voriconazole is a triazole antifungal that exhibits broad-spectrum activity and is a first-line agent for the treatment of Candida sp. infections (1), invasive aspergillosis (2), and other serious fungal infections. With increasing numbers of at-risk immunocompromised populations, such as those undergoing solid-organ transplantation or those with HIV infections, the incidence of invasive mycoses is on the rise (3, 4). Despite the advent of newer antifungals, Aspergillus sp. and Candida sp. infections have exhibited high mortality rates of 60% and 30%, respectively (5, 6).Recent published studies of voriconazole have shed light on the clinical relevance of therapeutic drug monitoring (TDM) for optimization of dosing based on voriconazole's highly variable pharmacokinetics (PK) and the resultant poor predictability of plasma concentrations (7,8). Subtherapeutic concentrations have been linked to higher failure rates in patients with life-threatening invasive fungal infections, and supratherapeutic concentrations are associated with neurological and hepatic toxicity (9-19). Voriconazole is primarily metabolized by CYP2C19, which commonly exhibits genetic polymorphism, leading to variable PK and leaving certain populations susceptible to decreased metabolism and increased plasma concentrations of voriconazole (20-23). Patients of Asian descent with polymorphisms in CYP2C19 have up to a 20% incidence of being poor metabolizers while this value is up to 5% for Caucasian and African American individuals (24). Poor metabolizers can have a PK exposure up to four times higher than that of homozygous comparators.Nonlinearity in voriconazole PK relating to saturable clearance mechanisms has been reported (8), which together with its extensive variability makes dosing profoundly challenging, especially when higher doses are used. Conve...

show abstract

“…As expected, AmB demonstrates excellent in vitro activity (Ͻ0.75 g/ml) against this organism. Voriconazole achieves excellent cerebrospinal fluid (CSF) penetration (about 50% of serum levels), has reasonably predictable serum levels, has a well-known toxicity profile, and is well tolerated by most patients (9)(10)(11). Similar to other azoles, there is an extensive list of medications that are contraindicated or should be given with caution when coadministered with voriconazole (11).…”

mentioning

confidence: 99%

Real-Time Treatment Guidelines: Considerations during the Exserohilum rostratum Outbreak in the United States

Pappas

Kontoyiannis²,

Perfect

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Multicenter Study of Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring

Cited by 240 publications

References 33 publications

Intensive care medicine research agenda on invasive fungal infection in critically ill patients

Intensive care medicine research agenda on invasive fungal infection in critically ill patients

Comparative Evaluation of the Predictive Performances of Three Different Structural Population Pharmacokinetic Models To Predict Future Voriconazole Concentrations

Real-Time Treatment Guidelines: Considerations during the Exserohilum rostratum Outbreak in the United States

Contact Info

Product

Resources

About