Do plasma concentrations obtained from early arterial blood sampling improve pharmacokinetic/pharmacodynamic modeling?

In pharmacokinetic/pharmacodynamic (PK/PD) modeling the first blood sample is usually taken 1 to 2 min after drug administration (late sampling). Ther efore, investigators have to extrapolate the plasma concentration to Time 0 . Extrapolation, however, erroneously assumes instantaneous and complete mi xing of drug in the central volume of distribution. We investigated whether plasma concentrations obtained from early arterial blood sampling would im prove PK/PD modeling. In 14 pigs, one of five neuromuscular blocking agents (NMBAs) was administered into the right ventricle within I sec and arteria l sampling was performed every 1.2 sec (1st min). The response of the tibia lis muscle was measured mechanomyographically. The influence of inclusion o f data from early arterial sampling on PK/PD modeling was determined. Furth ermore, the concentrations in the effect compartment at 50% block (EC50) de rived from modeling were compared to the measured concentration in plasma d uring a steady state 50% block. A very high peak in arterial plasma concent ration was seen within 20 sec after administration of the NMBA. Extensive m odeling revealed that plasma concentrations obtained from early arterial bl ood sampling improve PK/PD modeling. Independent of the type of modeling, t he EC50 and K-eO based on data sets that include early arterial blood sampl ing were, for all five NMBAs, significantly higher and tower respectively, than those based on data sets obtained from late sampling. Early arterial s ampling shows that the mixing of the NMBA in the central volume of distribu tion is incomplete. A parametric PD (sigmoid E-max) model could not describ e the time course of effect of the NMBAs adequately.