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Pharmacokinetic-pharmacodynamic model for propofol for broad application in anaesthesia and sedation

(2018) BRITISH JOURNAL OF ANAESTHESIA. 120(5). p.942-959
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Abstract
Background: Pharmacokinetic (PK) and pharmacodynamic (PD) models are used in target-controlled-infusion (TCI) systems to determine the optimal drug administration to achieve a desired target concentration in a central or effect-site compartment. Our aim was to develop a PK-PD model for propofol that can predict the bispectral index (BIS) for a broad population, suitable for TCI applications. Methods: Propofol PK data were obtained from 30 previously published studies, five of which also contained BIS observations. A PK-PD model was developed using NONMEM. Weight, age, post-menstrual age (PMA), height, sex, BMI, and presence/absence of concomitant anaesthetic drugs were explored as covariates. The predictive performance was measured across young children, children, adults, elderly, and high-BMI individuals, and in simulated TCI applications. Results: Overall, 15 433 propofol concentration and 28 639 BIS observations from 1033 individuals (672 males and 361 females) were analysed. The age range was from 27 weeks PMA to 88 yr, and the weight range was 0.68-160 kg. The final model uses age, PMA, weight, height, sex, and presence/absence of concomitant anaesthetic drugs as covariates. A 35-yr-old, 170 cm, 70 kg male (without concomitant anaesthetic drugs) has a V-1, V-2, V-3, CL, Q(2), Q(3), and keo of 6.28, 25.5, 273 litres, 1.79, 1.75, 1.11 litres min(-1), and 0.146 min(-1), respectively. The propofol TCI administration using the model matches well with recommendations for all age groups considered for both anaesthesia and sedation. Conclusions: We developed a PK-PD model to predict the propofol concentrations and BIS for broad, diverse population. This should be useful for TCI in anaesthesia and sedation.
Keywords
TARGET-CONTROLLED INFUSION, VS. SEQUENTIAL-ANALYSIS, BISPECTRAL INDEX, CHILDREN, REMIFENTANIL, PERFORMANCE, SIZE, LARYNGOSCOPY, MAINTENANCE, PAEDFUSOR, propofol, pharmacokinetics, pharmacology

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Chicago
Eleveld, DJ, Pieter Colin, AR Absalom, and Michel Struys. 2018. “Pharmacokinetic-pharmacodynamic Model for Propofol for Broad Application in Anaesthesia and Sedation.” British Journal of Anaesthesia 120 (5): 942–959.
APA
Eleveld, D., Colin, P., Absalom, A., & Struys, M. (2018). Pharmacokinetic-pharmacodynamic model for propofol for broad application in anaesthesia and sedation. BRITISH JOURNAL OF ANAESTHESIA, 120(5), 942–959.
Vancouver
1.
Eleveld D, Colin P, Absalom A, Struys M. Pharmacokinetic-pharmacodynamic model for propofol for broad application in anaesthesia and sedation. BRITISH JOURNAL OF ANAESTHESIA. 2018;120(5):942–59.
MLA
Eleveld, DJ, Pieter Colin, AR Absalom, et al. “Pharmacokinetic-pharmacodynamic Model for Propofol for Broad Application in Anaesthesia and Sedation.” BRITISH JOURNAL OF ANAESTHESIA 120.5 (2018): 942–959. Print.
@article{8574335,
  abstract     = {Background: Pharmacokinetic (PK) and pharmacodynamic (PD) models are used in target-controlled-infusion (TCI) systems to determine the optimal drug administration to achieve a desired target concentration in a central or effect-site compartment. Our aim was to develop a PK-PD model for propofol that can predict the bispectral index (BIS) for a broad population, suitable for TCI applications. 
Methods: Propofol PK data were obtained from 30 previously published studies, five of which also contained BIS observations. A PK-PD model was developed using NONMEM. Weight, age, post-menstrual age (PMA), height, sex, BMI, and presence/absence of concomitant anaesthetic drugs were explored as covariates. The predictive performance was measured across young children, children, adults, elderly, and high-BMI individuals, and in simulated TCI applications. 
Results: Overall, 15 433 propofol concentration and 28 639 BIS observations from 1033 individuals (672 males and 361 females) were analysed. The age range was from 27 weeks PMA to 88 yr, and the weight range was 0.68-160 kg. The final model uses age, PMA, weight, height, sex, and presence/absence of concomitant anaesthetic drugs as covariates. A 35-yr-old, 170 cm, 70 kg male (without concomitant anaesthetic drugs) has a V-1, V-2, V-3, CL, Q(2), Q(3), and keo of 6.28, 25.5, 273 litres, 1.79, 1.75, 1.11 litres min(-1), and 0.146 min(-1), respectively. The propofol TCI administration using the model matches well with recommendations for all age groups considered for both anaesthesia and sedation. 
Conclusions: We developed a PK-PD model to predict the propofol concentrations and BIS for broad, diverse population. This should be useful for TCI in anaesthesia and sedation.},
  author       = {Eleveld, DJ and Colin, Pieter and Absalom, AR and Struys, Michel},
  issn         = {0007-0912},
  journal      = {BRITISH JOURNAL OF ANAESTHESIA},
  keywords     = {TARGET-CONTROLLED INFUSION,VS. SEQUENTIAL-ANALYSIS,BISPECTRAL INDEX,CHILDREN,REMIFENTANIL,PERFORMANCE,SIZE,LARYNGOSCOPY,MAINTENANCE,PAEDFUSOR,propofol,pharmacokinetics,pharmacology},
  language     = {eng},
  number       = {5},
  pages        = {942--959},
  title        = {Pharmacokinetic-pharmacodynamic model for propofol for broad application in anaesthesia and sedation},
  url          = {http://dx.doi.org/10.1016/j.bja.2018.01.018},
  volume       = {120},
  year         = {2018},
}

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