PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF MIVACURIUM IN RATS

The pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of t he neuromuscular blocking agent mivacurium were evaluated separately i n two groups of rats receiving 0.6 mg kg(-1) of mivacurium in a 2.5-mi n intravenous continuous (iv) infusion. The PK parameters for mivacuri um were determined in the first group. A two-compartment model describ es the kinetics of mivacurium in plasma. The estimates of the apparent volume of distribution at steady-state and plasma clearance [mean(SE) ] were 650 (123) mL kg(-1) and 9.9 (0.75) mL min(-1) kg(-1), respectiv ely. In the second group, the evoked tibialis anterior muscle tension was monitored. The PK parameters derived from the first group were use d to compute mivacurium plasma concentrations (C) at the times the PD measurements were recorded in the second group. The concentration-neur omuscular effect [% depression of initial twitch tension (E)] relation ship was analyzed by two approaches. (1) The relationship of estimated effect site concentrations versus E; a sigmoidal E(max) model describ ed the effect compartment concentrations versus E relationship. The es timate [mean(SE)] of C-ess50 (steady-state plasma concentration elicit ing half of maximum E) was 0.65 (0.01) mu g mL(-1). The value [mean(SE )] of k(eo) (rate constant of equilibration between plasma and effect site) was estimated at 0.32 (0.03) min(-1). (2) The relationship of de scending limb C versus E; a sigmoidal E(max) model described such rela tionship. The estimate [mean(SE)] of C-50 (post-infusion C eliciting h alf of maximum E) was 0.57(0.03) mu g mL(-1). The PD properties of miv acurium were also evaluated in another two groups of animals receiving either 5- or 10-min continuous iv infusion; PK and PD parameters obta ined from the 2.5-min infusion experiments were used to predict the ti me course of fin the groups receiving 0.6 mg kg(-1) of mivacurium in 5 - and 10-min infusions; simulations using the estimated parameters ade quately describe the time course of E in those groups. The effect of m ivacurium on the mean arterial blood pressure (MAP) was also investiga ted; a 10% nonsignificant decrease (p > 0.05) in MAP was found in all groups.