Pharmacokinetic-pharmacodynamic modeling of propofol in children

Abstract

Background: The aim of this study was to identify the best model to describe pharmacokinetics and pharmacodynamics in prepubertal children and therefore to calculate the corresponding pharmacodynamic parameters. In addition, and to confirm our method, a group of postpubertal subjects was also studied.

Methods: Sixteen children (9.5 yr, range 6-12) and 13 adults (22 yr, range 13-35) were included. Induction was performed by plasma target-controlled infusion of propofol (6 microg/ml) based on the Kataria model in children and on the Schnider model in adults. The relationship of bispectral index to predicted concentrations was studied during induction using the Kataria, pediatric Marsh, Schüttler, and Schnider models in children. Because the best performance was obtained, strangely enough, with the Schnider model, the two groups were pooled to investigate influence of puberty on pharmacodynamic parameters (kE0 [plasma effect-site equilibration rate constant] and Ce50 [effect-site concentration corresponding with 50% of the maximal effect]). The time-to-peak effect was calculated, and the kE0 was determined for the Kataria model (nonlinear mixed-effects modeling; pkpdtools).

Results: In children, the predicted concentration/effect relationship was best described using the Schnider model. When the whole population was considered, a significant improvement in this model was obtained using puberty as a covariate for kE0 and Ce50. The time to peak effect, Tpeak (median, 0.71 [range, 0.37-1.64] and 1.73 [1.4-2.68] min), and the Ce50 (3.71 [1.88-4.4] and 3.07 [2.95-5.21] microg/ml) were shorter and higher, respectively, in children than in adults. The kE0 linked to the Kataria model was 4.6 [1.4-11] min.

Conclusions: In children, the predicted concentration/effect relationships were best described using the Schnider model described for adults compared with classic pediatric models. The study suggests that the Schnider model might be useful for propofol target-control infusion in children.