Achieving target voriconazole concentrations more accurately in children and adolescents

Michael Neely, Ashley Margol, Xiaowei Fu, Michael Van Guilder, David Bayard, Alan Schumitzky, Regina Orbach, Siyu Liu, Stan Louie, William Hope

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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 non-parametric population model with data from 141 previously richly sampled children and adults. We then used it in our multiple-model 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.).

Original languageEnglish (US)
Pages (from-to)3090-3097
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume59
Issue number6
DOIs
StatePublished - Jun 1 2015

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Pharmacokinetics
Drug Monitoring
Population
Pediatrics
Pharmaceutical Preparations
Voriconazole
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Achieving target voriconazole concentrations more accurately in children and adolescents. / Neely, Michael; Margol, Ashley; Fu, Xiaowei; Van Guilder, Michael; Bayard, David; Schumitzky, Alan; Orbach, Regina; Liu, Siyu; Louie, Stan; Hope, William.

In: Antimicrobial Agents and Chemotherapy, Vol. 59, No. 6, 01.06.2015, p. 3090-3097.

Research output: Contribution to journalArticle

Neely, M, Margol, A, Fu, X, Van Guilder, M, Bayard, D, Schumitzky, A, Orbach, R, Liu, S, Louie, S & Hope, W 2015, 'Achieving target voriconazole concentrations more accurately in children and adolescents', Antimicrobial Agents and Chemotherapy, vol. 59, no. 6, pp. 3090-3097. https://doi.org/10.1128/AAC.00032-15
Neely, Michael ; Margol, Ashley ; Fu, Xiaowei ; Van Guilder, Michael ; Bayard, David ; Schumitzky, Alan ; Orbach, Regina ; Liu, Siyu ; Louie, Stan ; Hope, William. / Achieving target voriconazole concentrations more accurately in children and adolescents. In: Antimicrobial Agents and Chemotherapy. 2015 ; Vol. 59, No. 6. pp. 3090-3097.
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