Pharmacokinetic and pharmacodynamic modelling with pancuronium

Abstract

The pharmacokinetics and pharmacodynamics of pancuronium were studied following intravenous infusion in eleven patients undergoing surgical anaesthesia. Measurement of the plasma concentrations (Cp) of the neuromuscular blocking agent ( NMBA ) and the concomitant intensities of paralysis allowed their simultaneous modelling. The pharmacokinetic parameters derived for pancuronium were in the range of previously reported values, except that the mean total systemic plasma clearance (0.79 +/- 0.28 ml X min-1 X kg-1) was reduced and the mean terminal phase half-life (169 min) was longer in these patients. Plasma concentration and % paralysis data were successfully fitted to a previously proposed pharmacodynamic model. This model assumes a separate effect compartment which exchanges drug directly with the central kinetic compartment (integrated effect model). The 'steady-state' Cp necessary to produce 50% paralysis ( ECpss (50] was estimated to be 0.21 +/- 0.08 micrograms X ml-1 (mechanical response) and 0.18 +/- 0.05 micrograms X ml-1 (EMG response). An analysis using the Hill equation of the Cp-response relationship, during and after the constant-rate infusion of pancuronium bromide, resulted in effective plasma concentrations for 50% paralysis ( ECp50 ) of 0.35 +/- 0.06 micrograms X ml-1 and 0.20 +/- 0.09 micrograms X ml-1, respectively, for mechanical twitch response. The corresponding values for EMG response were 0.32 +/- 0.06 micrograms X ml-1 and 0.17 +/- 0.06 micrograms X ml-1. Using this latter approach, the ECp50 estimated during onset of paralysis was significantly higher than that estimated during offset of paralysis (p less than 0.05); no such difference was apparent between this latter parameter and the ECpss (50) of the integrated effect model (p greater than 0.05). No significant differences were observed between any of the pharmacodynamic parameter estimates generated from the data obtained from the two methods of assessment of neuromuscular function (mechanical vs. EMG response) (p greater than 0.05).

East–West pathology agreement on precancerous liver lesions and early hepatocellular carcinoma #

“…Pharmacokinetic data that was below the detection limit of the LC–MS method were not included in statistical analyses. Hemodynamic data as a function of resulting plasma dobutamine concentration was correlated to sigmoidal distributions (Prism 5.04; GraphPad, La Jolla, California), which yielded minimum and maximum effects and the plasma concentration at 50% effect (EC 50 ) 19,20. Hemodynamic data taken with the Sequential Multiple Dosing Protocol were similarly fit to sigmoidal curves, which yielded a maximum effect and dose at 50% effect (ED 50 ).…”

Understanding the Hysteresis Loop Conundrum in Pharmacokinetic / Pharmacodynamic Relationships

“…There are a variety of examples in the literature that suggest this type of pharmacokinetic/ pharmacodynamic relationship as reported in Table 3 [80–102, 313–317, and 330]. A clockwise hysteresis may mechanistically manifest due to a variety of underlying mechanisms as discussed below.…”

Calculation of an effect compartment rate constant using recovery indices obtained with an isolated arm technique

“…This difference emphasizes the predominant influence of the context-sensitive half-life over the T ½ of the effect compartment, where the value in table 1 reflects the lack of pharmacokinetic influence, the relative purity of the effect compartment with the isolated arm technique, in the derivation of the "intrinsic" value for the rate constant. Atracurium Non-compartmental [11] 0.07 6.1 1.4 Two-compartment [12] 0.12 4.6 1.6 Two-compartment [13] 0.10 4.3 1.7 Non-compartmental [14] 0.12 3.4 1.8 Vecuronium Three-compartment [15] 0.10 5.5 1.5 Three-compartment [16] 0.17 5.8 1.5 Two-and three-compartment [17] 0.06 5.3 1.5 Non-compartmental [17] 0.09 3.9 1.8 Three-compartment [18] 0.11 --Rocuronium Three-compartment [19] 0.12 5.0 1.5 Pancuronium Two-and three-compartment [18] 0.48 5.5 1.5 Three-compartment [19] 0.11 4.8 1.6 Three-compartment [20] 0.15 --…”