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 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.