Therapeutic Drug Monitoring of Voriconazole

Brüggemann, Roger J. M.; Donnelly, J. Peter; Aarnoutse, Rob E.; Warris, Adilia; Blijlevens, Nicole M A; Mouton, Johan W.; Verweij, Paul E.; Burger, David M.

doi:10.1097/ftd.0b013e31817b1a95

Cited by 110 publications

(92 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…While it is more common in adults, nonlinear, saturated pharmacokinetic behavior is readily observed in children who receive doses higher than those that have been approved by regulatory agencies (16). This nonlinearity also makes the half-life and the time to steady state dependent on the dose and concentration, complicating the ability to compare steady-state trough concentrations to the accepted therapeutic range of 1 to 6 mg/liter (17) and resulting in either unnecessary delays in sampling or premature sampling and misinterpreted concentrations. Furthermore, intuitive or empirical voriconazole dose adjustments result in prolonged patient exposure to voriconazole outside the therapeutic range in up to half or more of children and adults (6,10).…”

mentioning

confidence: 99%

Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents

Neely

Margol

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

f Despite the documented benefit of voriconazole therapeutic drug monitoring, nonlinear pharmacokinetics make the timing of steady-state trough sampling and appropriate dose adjustments unpredictable by conventional methods. We developed a nonparametric population model with data from 141 previously richly sampled children and adults. We then used it in our multiplemodel Bayesian adaptive control algorithm to predict measured concentrations and doses in a separate cohort of 33 pediatric patients aged 8 months to 17 years who were receiving voriconazole and enrolled in a pharmacokinetic study. Using all available samples to estimate the individual Bayesian posterior parameter values, the median percent prediction bias relative to a measured target trough concentration in the patients was 1.1% (interquartile range, ؊17.1 to 10%). Compared to the actual dose that resulted in the target concentration, the percent bias of the predicted dose was ؊0.7% (interquartile range, ؊7 to 20%). Using only trough concentrations to generate the Bayesian posterior parameter values, the target bias was 6.4% (interquartile range, ؊1.4 to 14.7%; P ‫؍‬ 0.16 versus the full posterior parameter value) and the dose bias was ؊6.7% (interquartile range, ؊18.7 to 2.4%; P ‫؍‬ 0.15). Use of a sample collected at an optimal time of 4 h after a dose, in addition to the trough concentration, resulted in a nonsignificantly improved target bias of 3.8% (interquartile range, ؊13.1 to 18%; P ‫؍‬ 0.32) and a dose bias of ؊3.5% (interquartile range, ؊18 to 14%; P ‫؍‬ 0.33). With the nonparametric population model and trough concentrations, our control algorithm can accurately manage voriconazole therapy in children independently of steady-state conditions, and it is generalizable to any drug with a nonparametric pharmacokinetic model. (This study has been registered at ClinicalTrials.gov under registration no. NCT01976078.) V oriconazole is the approved first-line therapy for aspergillosis in patients who are at least 12 years of age in the United States and at least 2 years of age elsewhere. Numerous reports of studies in both adults (1-7), including a prospective randomized trial (8), and children (9-11) have documented improved outcomes when trough concentrations are maintained above 1 mg/liter, which is a readily measured clinical surrogate for the full area under the concentration-time curve (AUC) that drives efficacy (12-15).However, the pharmacokinetic behavior of voriconazole is complex and nonlinear, such that in many patients, small dose changes are associated with disproportionately large changes in the plasma concentrations of the drug. While it is more common in adults, nonlinear, saturated pharmacokinetic behavior is readily observed in children who receive doses higher than those that have been approved by regulatory agencies (16). This nonlinearity also makes the half-life and the time to steady state dependent on the dose and concentration, complicating the ability to compare steady-state trough concentrations to the accepted therapeu...

show abstract

mentioning

confidence: 99%

Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents

Neely

Margol

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…In addition, several other gaps in knowledge (e.g., sampling time for optimal drug monitoring, thresholds that correlate with clinical efficacy and toxic effects) must be filled before TDM of voriconazole can be fully utilized. As Brüggemann and others 35 suggested in a recent review article, the indication to use voriconazole TDM as a means to ensure optimal drug concentrations after intravenousto-oral step-down is probably weak. Nonetheless, this approach is supported by the results of a randomized study of patients with invasive aspergillosis, in which 71% of the patients receiving voriconazole but only 58% of those receiving amphotericin B had treatment success at the 12-week follow-up, despite intravenous-to-oral therapy step-down (from 4 mg/kg IV twice daily to 200 mg PO twice daily) after a median of 10 days of IV therapy, regardless of plasma concentration of the drug.…”

Section: Utility Of Drug Monitoring In Clinical Decision-makingmentioning

confidence: 99%

mentioning

confidence: 99%

“…Brüggemann and others 35 and Howard and others 36 also discussed the role of TDM for voriconazole specifically, the latter focusing exclusively on invasive aspergillosis. The review by Brüggemann and others 35 was the most comprehensive to date and provided extensive interpretation of current data regarding the relation between concentrations of voriconazole and efficacy and toxic effects in patients. Although most previous authors have arrived at similar conclusions regarding the use of TDM to determine the efficacy and toxic effects of voriconazole, to the current authors' knowledge, there has been no discussion of the most fundamental issues in evaluating TDM, including its practical applicability in a clinical environment.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Role of Therapeutic Drug Monitoring of Voriconazole in the Treatment of Invasive Fungal Infections

Kuo

Ensom

2009

CJHP

View full text Add to dashboard Cite

Background: Voriconazole is a broad-spectrum, second-generation triazole antifungal agent with demonstrated efficacy in the treatment of invasive fungal infections caused by Aspergillus spp. and Candida spp. Given the characteristically poor prognosis of patients with invasive fungal infections and the protracted duration of treatment required, therapeutic monitoring of voriconazole is, in theory, an attractive method to optimize antifungal therapy. Objective:To determine the utility of therapeutic drug monitoring for voriconazole. Methods:A previously published decision-making algorithm was used to assess the currently available literature on therapeutic drug monitoring of voriconazole.Results: Several analytical methods can be used to quantify plasma or serum concentrations of voriconazole. Reasons for therapeutic monitoring of this drug include wide variability both within and between individuals secondary to drug properties, drug-drug interactions, and disease states. Furthermore, voriconazole follows nonlinear pharmacokinetics with saturable hepatic clearance. Another potential factor in favour of therapeutic drug monitoring for voriconazole is genetic polymorphism of CYP2C19, whereby patients who are homozygous for poor metabolism (about 19% of non-Indian Asians) can have 4-fold greater exposure to voriconazole. The concentrations of this drug are also greater in patients with hepatic impairment. Drug-drug interactions with other substrates of CYP2C9, CYP2C19, and CYP3A4 can also alter voriconazole concentrations. However, the correlations between plasma concentrations of voriconazole and its efficacy and toxicity are not well defined. Although lower and upper target thresholds of 0.25-2 mg/L and 4-6 mg/L, respectively, have been suggested, studies to date have not been appropriately designed or powered to reveal any definitive association. Conclusions:Routine therapeutic drug monitoring of voriconazole is not recommended except in certain circumstances, such as lack of response to therapy or evidence of toxicity, in which case selective monitoring of voriconazole concentrations may be of clinical utility. Méthodes : Un algorithme de prise de décision publié a été utilisé pour évaluer la documentation actuellement disponible sur le suivi thérapeutique pharmacologique du voriconazole. Résultats :Plusieurs méthodes analytiques peuvent servir à quantifier les concentrations sériques ou plasmatiques de voriconazole. Les raisons de recourir au suivi thérapeutique pharmacologique de ce médicament sont notamment la grande variabilité intra et interindividuelle attribuable aux propriétés du médicament, aux interactions médicament-médicament et aux affections. De plus, le voriconazole a un comportement pharmacocinétique non linéaire en raison d'une clairance hépatique saturable. Un autre facteur potentiellement en faveur du suivi thérapeutique pharmacologique du voriconazole est le polymorphisme génétique du CYP2C19 qui, chez les patients homozygotes ayant un faible métabolisme (environ 19 % des Asiatiques ...

show abstract

“…Voriconazole has a nonlinear pharmacokinetic profile with a wide inter-and intraindividual variety (117). The extensive metabolism of voriconazole is primarily mediated by CYP2C19 and CYP3A as well as by CYP2C9 to a lesser extent.…”

Section: Antimicrobicsmentioning

confidence: 99%

Herb–Drug Interactions with St John’s Wort (Hypericum perforatum): an Update on Clinical Observations

Borrelli

Izzo

2009

AAPS J

232

190

View full text Add to dashboard Cite

Abstract. St John's wort (SJW) extracts, prepared from the aerial parts of Hypericum perforatum, contain numerous pharmacologically active ingredients, including naphthodianthrones (e.g., hypericin and its derivatives), phloroglucinols derivatives (e.g., hyperforin, which inhibits the reuptake of a number of neurotransmitters, including serotonin), and flavonoids. Such extracts are widely used for the treatment of mild-to-moderate depression. As a monotherapy, SJW has an encouraging safety profile. However, relevant and, in some case, life-threatening interactions have been reported, particularly with drugs which are substrate of cytochrome P450 and/or P-glycoprotein. Well-documented SJW interactions include (1) reduced blood cyclosporin concentration, as suggested by multiple case reports as well as by clinical trials, (2) serotonin syndrome or lethargy when SJW was given with serotonin reuptake inhibitors, (3) unwanted pregnancies in women while using oral contraceptives and SJW, and (4) reduced plasma drug concentration of antiretroviral (e.g., indinavir, nevirapine) and anticancer (i.e., irinotecan, imatinib) drugs. Hyperforin, which is believed to contribute to the antidepressant action of St John's wort, is also strongly suspected to be responsible of most of the described interactions.

show abstract

Therapeutic Drug Monitoring of Voriconazole

Cited by 110 publications

References 67 publications

Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents

Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents

Role of Therapeutic Drug Monitoring of Voriconazole in the Treatment of Invasive Fungal Infections

Herb–Drug Interactions with St John’s Wort (Hypericum perforatum): an Update on Clinical Observations

Contact Info

Product

Resources

About