TY - JOUR
T1 - Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil I. Model development
AU - Minto, Charles F.
AU - Schnider, Thomas W.
AU - Egan, Talmage D.
AU - Youngs, Elizabeth
AU - Lemmens, Harry J.M.
AU - Gambus, Pedro L.
AU - Billard, Valerie
AU - Hoke, John F.
AU - Moore, Katherine H.P.
AU - Hermann, David J.
AU - Muir, Keith T.
AU - Mandema, Jaap W.
AU - Shafer, Steven L.
PY - 1997/1/1
Y1 - 1997/1/1
N2 - Background: Previous studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short-acting opioid remifentanil. Methods: Sixty-five healthy adults (38 men and 27 women) ages 20 to 85 y received remifentanil by constant-rate infusion of 1 to 8 μg · kg-1 · min-1 for 4 to 20 min. Frequent arterial blood samples were drawn and assayed for remifentanil concentration. The electroencephalogram was used as a measure of drug effect. Population pharmacokinetic and pharmacodynamic modeling was performed using the software package NONMEM. The influence of volunteer covariates were analyzed using a generalized additive model. The performances of the simple (without covariates) and complex (with covariates) models were evaluated prospectively in all additional 15 healthy participants ages 41 to 84 y. Results: The parameters for the simple three-compartment pharmacokinetic model were V1 = 4.98 l, V2 = 9.01 l, V3 = 6.54 l, Cl1 = 2.46 l/min, Cl2 = 1.69 l/min, and Cl3 = 0.065 l/min. Age and lean body mass were significant covariates. From the ages of 20 to 85 y, V1 and Cl1 decreased by approximately 25% and 33%, respectively. The parameters for the simple sigmoid E(max) pharmacodynamic model were k(c0) · 0.516 min-1, E50 = 20 Hz, E(max) = 5.62 Hz, EC50 = 11.2 ng/ml, and γ = 2.51. Age was a significant covariate of EC50 and k(c0), with both decreasing by approximately 50% for the age range studied. The complex pharmacokinetic - pharmacodynamic model performed better than did the simple model when applied prospectively. Conclusions: This study identified (1) an effect of age on the pharmacokinetics and pharmacodynamics of remifentanil; (2) an effect of lean body mass on the pharmacokinetic parameters; and (3) no influence of gender on any pharmacokinetic or pharmacodynamic parameter.
AB - Background: Previous studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short-acting opioid remifentanil. Methods: Sixty-five healthy adults (38 men and 27 women) ages 20 to 85 y received remifentanil by constant-rate infusion of 1 to 8 μg · kg-1 · min-1 for 4 to 20 min. Frequent arterial blood samples were drawn and assayed for remifentanil concentration. The electroencephalogram was used as a measure of drug effect. Population pharmacokinetic and pharmacodynamic modeling was performed using the software package NONMEM. The influence of volunteer covariates were analyzed using a generalized additive model. The performances of the simple (without covariates) and complex (with covariates) models were evaluated prospectively in all additional 15 healthy participants ages 41 to 84 y. Results: The parameters for the simple three-compartment pharmacokinetic model were V1 = 4.98 l, V2 = 9.01 l, V3 = 6.54 l, Cl1 = 2.46 l/min, Cl2 = 1.69 l/min, and Cl3 = 0.065 l/min. Age and lean body mass were significant covariates. From the ages of 20 to 85 y, V1 and Cl1 decreased by approximately 25% and 33%, respectively. The parameters for the simple sigmoid E(max) pharmacodynamic model were k(c0) · 0.516 min-1, E50 = 20 Hz, E(max) = 5.62 Hz, EC50 = 11.2 ng/ml, and γ = 2.51. Age was a significant covariate of EC50 and k(c0), with both decreasing by approximately 50% for the age range studied. The complex pharmacokinetic - pharmacodynamic model performed better than did the simple model when applied prospectively. Conclusions: This study identified (1) an effect of age on the pharmacokinetics and pharmacodynamics of remifentanil; (2) an effect of lean body mass on the pharmacokinetic parameters; and (3) no influence of gender on any pharmacokinetic or pharmacodynamic parameter.
KW - Analgesics, opioids: G187084B; remifentanil
KW - Electroencephalogram: spectral edge
KW - Pharmacodynamics: modeling; remifentanil
KW - Pharmacokinetics: generalized additive models; mammillary models; population: remifentanil
UR - http://www.scopus.com/inward/record.url?scp=0031030419&partnerID=8YFLogxK
U2 - 10.1097/00000542-199701000-00004
DO - 10.1097/00000542-199701000-00004
M3 - Article
C2 - 9009935
AN - SCOPUS:0031030419
SN - 0003-3022
VL - 86
SP - 10
EP - 23
JO - Anesthesiology
JF - Anesthesiology
IS - 1
ER -