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An allometric model of remifentanil pharmacokinetics and pharmacodynamics

Douglas J Eleveld, Johannes H Proost, Hugo Vereecke, Anthony R Absalom, Erik Olofsen, Jaap Vuyk and Michel Struys UGent (2017) ANESTHESIOLOGY. 126(6). p.1005-1018
abstract
Background: Pharmacokinetic and pharmacodynamic models are used to predict and explore drug infusion schemes and their resulting concentration profiles for clinical application. Our aim was to develop a pharmacokinetic-pharmacodynamic model for remifentanil that is accurate in patients with a wide range of age and weight. Methods: Remifentanil pharmacokinetic data were obtained from three previously published studies of adults and children, one of which also contained pharmacodynamic data from adults. NONMEM was used to estimate allometrically scaled compartmental pharmacokinetic and pharmacodynamic models. Weight, age, height, sex, and body mass index were explored as covariates. Predictive performance was measured across young children, children, young adults, middle-aged, and elderly. Results: Overall, 2,634 remifentanil arterial concentration and 3,989 spectral-edge frequency observations from 131 individuals (55 male, 76 female) were analyzed. Age range was 5 days to 85 yr, weight range was 2.5 to 106 kg, and height range was 49 to 193 cm. The final pharmacokinetic model uses age, weight, and sex as covariates. Parameter estimates for a 35-yr-old, 70-kg male (reference individual) are: V1, 5.81 l; V2, 8.82 l; V3, 5.03 l; CL, 2.58 l/min; Q2, 1.72 l/min; and Q3, 0.124 l/min. Parameters mostly increased with fat-free mass and decreased with age. The pharmacodynamic model effect compartment rate constant (ke0) was 1.09 per minute (reference individual), which decreased with age. Conclusions: We developed a pharmacokinetic-pharmacodynamic model to predict remifentanil concentration and effect for a wide range of patient ages and weights. Performance exceeded the Minto model over a wide age and weight range.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
VS. SEQUENTIAL-ANALYSIS, PREDICTIVE PERFORMANCE, PEDIATRIC-PATIENTS, PROPOFOL, OBESE, POPULATION, SURGERY, SIZE, CHILDREN, PLASMA
journal title
ANESTHESIOLOGY
Anesthesiology
volume
126
issue
6
pages
1005 - 1018
Web of Science type
Article
Web of Science id
000402744500004
ISSN
0003-3022
1528-1175
DOI
10.1097/ALN.0000000000001634
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
8532524
handle
http://hdl.handle.net/1854/LU-8532524
date created
2017-09-28 08:40:20
date last changed
2017-10-25 11:57:21
@article{8532524,
  abstract     = {Background: Pharmacokinetic and pharmacodynamic models are used to predict and explore drug infusion schemes and their resulting concentration profiles for clinical application. Our aim was to develop a pharmacokinetic-pharmacodynamic model for remifentanil that is accurate in patients with a wide range of age and weight. 
Methods: Remifentanil pharmacokinetic data were obtained from three previously published studies of adults and children, one of which also contained pharmacodynamic data from adults. NONMEM was used to estimate allometrically scaled compartmental pharmacokinetic and pharmacodynamic models. Weight, age, height, sex, and body mass index were explored as covariates. Predictive performance was measured across young children, children, young adults, middle-aged, and elderly. 
Results: Overall, 2,634 remifentanil arterial concentration and 3,989 spectral-edge frequency observations from 131 individuals (55 male, 76 female) were analyzed. Age range was 5 days to 85 yr, weight range was 2.5 to 106 kg, and height range was 49 to 193 cm. The final pharmacokinetic model uses age, weight, and sex as covariates. Parameter estimates for a 35-yr-old, 70-kg male (reference individual) are: V1, 5.81 l; V2, 8.82 l; V3, 5.03 l; CL, 2.58 l/min; Q2, 1.72 l/min; and Q3, 0.124 l/min. Parameters mostly increased with fat-free mass and decreased with age. The pharmacodynamic model effect compartment rate constant (ke0) was 1.09 per minute (reference individual), which decreased with age. 
Conclusions: We developed a pharmacokinetic-pharmacodynamic model to predict remifentanil concentration and effect for a wide range of patient ages and weights. Performance exceeded the Minto model over a wide age and weight range.},
  author       = {Eleveld, Douglas J and Proost, Johannes H and Vereecke, Hugo and Absalom, Anthony R and Olofsen, Erik and Vuyk, Jaap and Struys, Michel},
  issn         = {0003-3022},
  journal      = {ANESTHESIOLOGY},
  keyword      = {VS. SEQUENTIAL-ANALYSIS,PREDICTIVE PERFORMANCE,PEDIATRIC-PATIENTS,PROPOFOL,OBESE,POPULATION,SURGERY,SIZE,CHILDREN,PLASMA},
  language     = {eng},
  number       = {6},
  pages        = {1005--1018},
  title        = {An allometric model of remifentanil pharmacokinetics and pharmacodynamics},
  url          = {http://dx.doi.org/10.1097/ALN.0000000000001634},
  volume       = {126},
  year         = {2017},
}

Chicago
Eleveld, Douglas J, Johannes H Proost, Hugo Vereecke, Anthony R Absalom, Erik Olofsen, Jaap Vuyk, and Michel Struys. 2017. “An Allometric Model of Remifentanil Pharmacokinetics and Pharmacodynamics.” Anesthesiology 126 (6): 1005–1018.
APA
Eleveld, D. J., Proost, J. H., Vereecke, H., Absalom, A. R., Olofsen, E., Vuyk, J., & Struys, M. (2017). An allometric model of remifentanil pharmacokinetics and pharmacodynamics. ANESTHESIOLOGY, 126(6), 1005–1018.
Vancouver
1.
Eleveld DJ, Proost JH, Vereecke H, Absalom AR, Olofsen E, Vuyk J, et al. An allometric model of remifentanil pharmacokinetics and pharmacodynamics. ANESTHESIOLOGY. 2017;126(6):1005–18.
MLA
Eleveld, Douglas J, Johannes H Proost, Hugo Vereecke, et al. “An Allometric Model of Remifentanil Pharmacokinetics and Pharmacodynamics.” ANESTHESIOLOGY 126.6 (2017): 1005–1018. Print.