Characterization of the pharmacokinetics and pharmacodynamics of the stereoisomers of mivacurium in humans and dogs

Abstract

The issue of stereoisomers in drug development and therapy is becoming increasingly important as a more complete understanding of differences between drug isomers is developed with respect to pharmacokinetics and pharmacodynamics. Mivacurium chloride is a short-acting, non-depolarizing neuromuscular blocking agent. Mivacurium is a mixture of three stereoisomers: the trans-trans, the cis-trans, and the cis-cis diester. The pharmacokinetics and pharmacodynamics of these isomers were investigated in humans and dogs to develop a mathematical model. This model may be used in a closed-loop system to optimize drug administration and patient monitoring and, henceforth, to improve clinical outcomes. A bolus dose (0.01-0.02 mg/kg) and two infusion rates (1.0-1.5 {dollar}\mu{dollar}g/kg/min) of mivacurium were administered to four beagle dogs. Dogs were anesthetized with 5% isofluorane. NMB was assessed by train-of four (TOF) and single twitch stimulation. Each dog received two treatments with a washout period of ten days. Blood samples were collected up to 6 min after the bolus dose, for 4 min after the administration of each infusion and during recovery. Eleven subjects agreed to participate in a pharmacodynamics study. Patients received a bolus dose (0.10-0.20 mg/kg) and sequential infusions of mivacurium as needed to maintain twitch height (TH) 10% baseline. NMB was assessed by TH depression after TOF stimulation. Another group of five subjects, agreed to participate in a pharmacokinetics-pharmacodynamics study. The dosing schedule and monitoring ofthe paralysis was as previously discussed. Blood samples were collected up to 10 min after the bolus dose, and up to 10 min after the administration of the last infusion. Samples were analyzed using a stereospecific KPLC-fluorescence method. Modeling of the data was accomplished using ADAPT II. The pharmacokinetics of the two major isomers of mivacurium in dogs were best described by a two-compartment model. TOF was a more sensitive measure of onset and offset of NMB than TH. Onset of action showed dose-dependence. The pharmacokinetics of isomers of mivacurium were best described by a two-compartment model in three of the five patients. The model developed with the first eleven patients was predictive of the concentration-effect (CE) relationship. The CE relationship was best described by a sigmoid E{dollar}\rm\sb{lcub}max{rcub}{dollar} model in humans and dogs. The value of pharmacokinetics-pharmacodynamics models should be to allow better insight into the principles governing the time course of drug action and to get a better predictive estimate of the patients response to dosing and to improve drug therapy outcomes.