Modeling the pharmacokinetics and pharmacodynamics of sevoflurane using compartment models in children and adults.

Abstract

Sevoflurane pharmacokinetics have been traditionally described using physiological models, while pharmacodynamics employed the use of minimal alveolar concentration. The integrated pharmacokinetic-pharmacodynamic relationship of sevoflurane in both adults and children was reviewed using compartment models. We wished to delineate age-related changes in both pharmacokinetics and pharmacodynamics. The bispectral index and sevoflurane endtidal concentration were continuously measured in 50 patients, aged 3-71years, scheduled for minor surgery. During maintenance of anesthesia and after stable bispectral index values of 60-65 were obtained, the inspired concentration of sevoflurane was increased to 5 vol % for 5minutes or until BIS 40 and then decreased. Data were analyzed using mammillary compartments with nonlinear mixed effects population modeling. The covariate effects of age and size were investigated. A three-compartment PK model adequately described sevoflurane pharmacokinetics. Size standardization using allometry explained clearance and volume changes with age. The equilibration half-time (1.48minutes) increased with age, but could be predicted using allometry in those under 40years. The effect site concentration eliciting half the maximum response at age 40years was 1.3% (95%CI 1.22, 1.42) decreased with age from 1.6% at 3years to 1.1% at 70years. Pharmacokinetic compartment models offer an alternative method to describe inhalation anesthetic drug disposition and effects.