Population pharmacokinetic and pharmacodynamic model of propofol externally validated in children

J Pharmacokinet Pharmacodyn. 2015 Apr;42(2):163-77. doi: 10.1007/s10928-015-9408-2. Epub 2015 Feb 28.

Abstract

There have been no pharmacokinetic parameters and blood-brain equilibration rate constant (k e0) of propofol obtained in a single population of children, by which propofol can be administered using a target effect-site concentration controlled infusion. Thirty-nine, American Society of Anesthesiologists Physical Status 1-2 children aged 2-12 years were given an intravenous bolus of propofol (3 mg kg(-1)), followed by infusion (200 µg kg(-1) min(-1)). Arterial drug concentrations and bispectral index (BIS) values were measured. Population pharmacokinetic and pharmacodynamic analysis was performed using nonlinear mixed effects modeling. External model validation was performed in a separate population of children. A two-compartment model and a sigmoid E max model directly linked by an effect compartment well described the time courses of propofol concentration and BIS. The estimates of parameters were: V 1 (L) = 1.69, V 2 (L) = 27.2 + 0.929 × (weight - 25), Cl (L min(-1)) = 0.893 × (weight/23.6)(0.966), Q (L min(-1)) = 1.3; E 0 = 76.9; E max = 35.4, Ce 50 (μg mL(-1)) = 3.47 - (0.095 × age) - (1.63 × mean infusion rate of remifentanil in µg kg(-1) min(-1)); γ = 2.1; and k e0 (min(-1)) = 0.371. Pooled biases (95 % CI) of the target effect-site concentration controlled infusion system of propofol was -20.2 % (-23.3 to -18.1 %) and pooled inaccuracy was 30.4 % (28.6-32.7 %). Pooled biases of BIS prediction was -6.8 % (-9.1 to -4.1 %) and pooled inaccuracies was 19.1 % (17.5-20.9 %).The altered weight-based dose requirements of propofol are well described pharmacokinetically, and pharmacodynamically. Predictive performances of the TCI system in this study were clinically acceptable.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthetics, Intravenous / administration & dosage*
  • Anesthetics, Intravenous / pharmacokinetics*
  • Brain / metabolism
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Infusions, Intravenous / methods
  • Injections, Intravenous / methods
  • Male
  • Models, Biological
  • Piperidines / administration & dosage
  • Piperidines / pharmacokinetics
  • Propofol / administration & dosage*
  • Propofol / pharmacokinetics*
  • Remifentanil

Substances

  • Anesthetics, Intravenous
  • Piperidines
  • Remifentanil
  • Propofol