Population pharmacokinetic and pharmacodynamic model of propofol externally validated in children

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 A mu g 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 x (weight - 25), Cl (L min(-1)) = 0.893 x (weight/23.6)(0.966), Q (L min(-1)) = 1.3; E (0) = 76.9; E (max) = 35.4, Ce (50) (mu g mL(-1)) = 3.47 - (0.095 x age) - (1.63 x mean infusion rate of remifentanil in A mu g kg(-1) min(-1)); gamma = 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.