<i><scp>CYP</scp>2C19</i> Polymorphisms and Therapeutic Drug Monitoring of Voriconazole: Are We Ready for Clinical Implementation of Pharmacogenomics?

Obeng, Aniwaa Owusu; Egelund, Eric F.; Alsultan, Abdullah; Peloquin, Charles A.; Johnson, Julie A.

doi:10.1002/phar.1400

Cited by 108 publications

(81 citation statements)

References 67 publications

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“…Moreover, none of the patients having a combined genetic score of Ͻ2 presented an initial VRC C min inferior to the efficacy threshold fixed at 1 mg/liter, while 47% of the patients with a combined genetic score of Ն2 had a subtherapeutic initial VRC C min . These data suggest that this combined genetic score could help to individualize the VRC dose from the first administration onwards, as recently suggested for CYP2C19 (13,38), and reduce the risk of out-of-range VRC C min at the first determination.…”

Section: Discussionsupporting

confidence: 62%

Variability of Voriconazole Plasma Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Cytochrome P450 Polymorphisms and Comedications on Initial and Subsequent Trough Levels

Gautier-Veyret

Fonrose

Tonini

et al. 2015

Antimicrob Agents Chemother

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f Voriconazole (VRC) plasma trough concentrations (C min ) are highly variable, and this could affect treatment efficacy and safety in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). We aimed to describe the intra-and interindividual variation of VRC C min throughout the course of VRC therapy and to identify the determinants of this variation. Clinical data, medications, and VRC C min (n ‫؍‬ 308) of 33 AHSCT patients were retrospectively collected. Cytochrome P450 (CYP450) genotypes of CYP2C19, CYP3A4, and CYP3A5 patients were retrospectively determined before allografting, and a combined genetic score was calculated for each patient. The higher the genetic score, the faster the metabolism of the patient. The VRC C min inter-and intraindividual coefficients of variation were 84% and 68%, respectively. The VRC dose (D) was correlated to VRC C min (r ‫؍‬ 0.412, P < 0.0001) only for oral administration. The administration route and the genetic score significantly affected the initial VRC C min . Considering oral therapy, patients with a genetic score of <2 had higher initial VRC C min /D than patients with a genetic score of >2 (P ‫؍‬ 0.009). Subsequent VRC C min remained influenced by the genetic score (P ‫؍‬ 0.004) but were also affected by pump proton inhibitor comedication (P < 0.0001). The high variability of VRC C min in AHSCT patients is partially explained by the route of administration, treatment with pump proton inhibitors, and the combined genetic score. This study suggests the interest in combined genetic score determination to individualize a priori the VRC dose and underlines the need for longitudinal therapeutic drug monitoring to adapt subsequent doses to maintain the VRC C min within the therapeutic range.

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Section: Discussionsupporting

confidence: 62%

Variability of Voriconazole Plasma Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Cytochrome P450 Polymorphisms and Comedications on Initial and Subsequent Trough Levels

Gautier-Veyret

Fonrose

Tonini

et al. 2015

Antimicrob Agents Chemother

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“…Interestingly, neither we nor the others (1,22) included the CYP2C19 genotype as a covariate. While there is no doubt that polymorphisms in this gene affect the disposition of voriconazole in adults and children (33,34), we believe that the therapeutic index of the drug is not sufficiently narrow that the accuracy of the very first dose is critical. We have shown for tacrolimus that the influence of CYP3A5 polymorphisms is minimal after concentrations are available (23).…”

Section: Figmentioning

confidence: 82%

“…Measured concentrations reflect the phenotypic characteristics of the individual patient, which is the sum of all genetic influences, measured or unmeasured, and other nongenetic influences. Therefore, while knowledge of the patient's CYP2C19 genotype a priori may improve the accuracy of initial dosing (33), robust therapeutic drug management with a tool like multiple-model Bayesian adaptive control is likely to play a much more important role beyond the first day or two of therapy.…”

Section: Figmentioning

confidence: 99%

Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents

Neely

Margol

et al. 2015

Antimicrob Agents Chemother

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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...

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“…The prospect of pharmacogenomics testing has been explored for a myriad of medications including CYP2C19 genotyping to aid voriconazole dosing [12]. Guidelines from the Royal Dutch Pharmacists Association Pharmacogenetics Working Group, recommend monitoring voriconazole serum concentrations in patients expressing the CYP2C19 poor metabolizer (PM) and CYP2C19 intermediate metabolizer phenotypes [13].…”

Section: Introductionmentioning

confidence: 99%

“…Common side effects of voriconazole include hepatotoxicity, neurotoxicity, blurry vision, skin rash and hyperfluorosis [14]. Some of these adverse effects are more likely to occur at higher than necessary voriconazole serum/plasma concentrations, while low voriconazole levels may result in therapeutic failure [12]. As such, voriconazole therapeutic drug monitoring (TDM) has become commonplace in the management of serious fungal infections.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Drug Monitoring and Genotypic Screening in the Clinical Use of Voriconazole

Moriyama

Kadri

Henning

et al. 2015

Curr Fungal Infect Rep

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Voriconazole is an antifungal triazole that is the first line agent for treatment of invasive aspergillosis. It is metabolized by CYP2C19, CYP2C9, and CYP3A4 and demonstrates wide interpatient variability in serum concentrations. Polymorphisms in CYP2C19 contribute to variability in voriconazole pharmacokinetics. Here, evidence is examined for the use of voriconazole therapeutic drug monitoring (TDM) and the role of CYP2C19 genotyping in voriconazole dosing. The majority of studies exploring the impact of voriconazole TDM on efficacy and safety have found TDM to be beneficial. However, most of these studies are observational, with only one being a randomized controlled trial. High-volume multicenter randomized controlled trials of TDM are currently not available to support definitive guidelines. There is a significant relationship in healthy volunteers between CYP2C19 genotype and voriconazole pharmacokinetics, but this association is markedly less visible in actual patients. While CYP2C19 genotype data may explain variability of voriconazole serum levels, they alone are not sufficient to guide initial dosing. The timeliness of availability of CYP2C19 genotype data in treatment of individual patients also remains challenging. Additional studies are needed before implementation of CYP2C19 genotyping for voriconazole dosing into routine clinical care.

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CYP2C19 Polymorphisms and Therapeutic Drug Monitoring of Voriconazole: Are We Ready for Clinical Implementation of Pharmacogenomics?

Cited by 108 publications

References 67 publications

Variability of Voriconazole Plasma Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Cytochrome P450 Polymorphisms and Comedications on Initial and Subsequent Trough Levels

Variability of Voriconazole Plasma Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Cytochrome P450 Polymorphisms and Comedications on Initial and Subsequent Trough Levels

Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents

Therapeutic Drug Monitoring and Genotypic Screening in the Clinical Use of Voriconazole

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