PHARMACOKINETICS AND PHARMACODYNAMICS OF REMIFENTANIL .2. MODEL APPLICATION

Background: The pharmacokinetics and pharmacodynamics of remifentanil were studied in 65 healthy volunteers using the electroencephalogram ( EEG) to measure the opioid effect.(1) In a companion article, the auth ors developed complex population pharmacokinetic and pharmacodynamic m odels that incorporated age and lean body mass (LBM) as significant co variates and characterized intersubject pharmacokinetic and pharmacody namic variability, In the present article, the authors determined whet her remifentanil dosing should be adjusted according to age and LBM, o r whether these covariate effects were overshadowed by the interindivi dual variability present in the pharmacokinetics and pharmacodynamics, Methods: Based on the typical pharmacokinetic and pharmacodynamic par ameters, nomograms for bolus dose and infusion rates at each age and L BM were derived. Three populations of 500 individuals each, ages 20, 5 0, and 80 yr, were simulated base on the interindividual variances in model parameters as estimated by the NONMEM software package, The peak EEG effect in response to a bolus, the steady-state EEG effect in res ponse to an infusion, and the time course of drug effect were examined in each of the three populations. Simulations were performed to exami ne the time necessary to achieve a 20%, 50%, and 80% decrease in remif entanil effect site concentration after a variable-length infusion, Th e variability in the time for a 50% decrease in effect site concentrat ions was examined in each of the three simulated populations. Titratab ility using a constant-rate infusion was also examined, Results: After a bolus dose, the age-related changes in V-1 and k(c0) nearly offset each other. The peak effect site concentration reached after a bolus d ose does not depend on age, However, the peak effect site concentratio n occurs later in elderly individuals. Because the EEG shows increased brain sensitivity to opioids with increasing age, an 80-yr-old person required approximately one half the bolus dose of a 20-yr old of simi lar LBM to reach the same peak EEG effect. Failure to adjust the bolus dose for age resulted in a more rapid onset of EEG effect and prolong ed duration of EEG effect in the simulated elderly population. The inf usion rate required to maintain 50% EEG effect in a typical 80-yr-old is approximately one third that requited in a typical 20-yr-old. Failu re to adjust the infusion rate for age resulted in a more rapid onset of EEG effect and more profound steady-state EEG effect in the simulat ed elderly population, The typical times required for remifentanil eff ect site concentrations to decrease by 20%, 50%, and 80% after prolong ed administration are rapid and little affected by age or duration of infusion, These simulations suggest that the time required for a decre ase in effect site concentrations will be more variable in the elderly , As a result, elderly patients may occasionally have a slower emergen ce from anesthesia than expected, A step change in the remifentanil in fusion rate resulted in a rapid and predictable change of EEG effect i n both the young and the elderly. Conclusions: Based on the EEG model, age and LBM are significant demographic factors that must be consider ed when determining a dosage regimen for remifentanil, This remains tr ue even when interindividual pharmacokinetic and pharmacodynamic varia bility are incorporated in the analysis.