COMPUTER-CONTROLLED INFUSION OF INTRAVENOUS DEXMEDETOMIDINE HYDROCHLORIDE IN ADULT HUMAN VOLUNTEERS

Background: This investigation extended the pharmacokinetic analysis o f our previous study, of intravenous dexmedetomidine in 10 healthy mal e volunteers, and prospectively tested the resulting compartmental pha rmacokinetics in an additional six subjects using a computer-controlle d infusion pump (CCIP) to target four different plasma concentrations of dexmedetomidine for 30 min at each concentration. Methods: A three- compartment mammary pharmacokinetic model best described the intraveno us dexmedetomidine concentration versus time profile following the 5 m in intravenous infusion of 2 mug/kg in our previous study. Nonlinear r egression was performed using both two-stage and pooled data technique s to determine the population pharmacokinetics. The pooled technique a llowed covariates, such as weight, age, and height of the subjects, to be incorporated into the nonlinear regression to test the hypothesis that these additional covariates would reduce the residual error betwe en the measured concentrations and the predicted values. Results: The addition of age, weight, lean body mass, and body surface area as cova riates of the pharmacokinetic parameters did not improve the predictiv e value of the model. However, the model was improved when subject hei ght was a covariate of the volume in the central compartment. The resi dual error in the pharmacokinetic model was markedly lower with the po oled versus the two-stage approach. The following pharmacokinetic valu es were obtained from the pooled analysis of the zero-order dexmedetom idine infusion: V1 = 8.05, V2 = 12.4, V3 = 175 (L), Cl1 = (0.0101heig ht [cm]) -1.33, Cl2 = 2.05, and Cl3 = 2.0 (L/min). Prospective evaluat ion of the pooled pharmacokinetic parameters using a computer-controll ed infusion in six healthy volunteers showed the precision (average [( absolute error)/measured concentration]) of the CCIP to be 31.5% and t he bias (average [error/measured concentration]) to be -22.4%. A poole d regression of the combined CCIP and zero-order data confirmed that t he covariate, height (cm), was related in linear fashion to Cl1. A str iking nonlinearity of dexmedetomidine pharmacokinetics related to conc entration was observed during the CCIP infusion. The final pharmacokin etic values for the entire data set were: V1 = 7.99, V2 = 13.8, V3 = 1 87 (L), Cl1 = (0.00791height [cm]) -0.927, Cl2 = 2.26, and Cl3 = 1.99 (L/min). Conclusions. Pharmacokinetics of dexmedetomidine are best de scribed by a three-compartment model. Addition of age, weight, lean bo dy mass, and body surface area do not improve the predictive value of the model. Additional improvement in CCIP accuracy for dexmedetomidine infusions would require magnification modification of the model based on the targeted concentration.