Pharmacokinetic analysis of the effect of vecuronium in surgical patients: pharmacokinetic and pharmacodynamic modeling without plasma concentrations.

Abstract

Methods of the kinetic analysis of vecuronium based on effect only were developed but have been limited by the short time period of the studies. Using a multicompartment model and sequential dosing, the authors studied the ability of tests to determine most pharmacokinetic and pharmacodynamic parameters of vecuronium without measuring plasma concentrations. The time course of neuromuscular blockade by successive bolus doses of vecuronium was recorded using electromyography. Inhibition of neuromuscular transmission by vecuronium was modeled by a biexponential decline in the concentrations in the central compartment and first-order transfer between the central and the effect compartments responsible for the inhibition of the first (T1) and fourth (T4) responses to train-of-four stimulation. The time course of the effect of vecuronium was described well by the model. The mean half-lives of equilibration between plasma and the effect compartments to inhibit T1 and T4 were 2.5 and 3.2 min, respectively. The mean half-lives of distribution and elimination from the central compartment were 7.7 and 7.8 min, respectively. From the kinetic and dynamic parameters calculated after two and three doses, the time taken to recover to 50% of the maximal block of T1 was predicted for the succeeding dose. The mean prediction errors (100 x [absolute difference between actual and predicted times]/actual) were 13.6% (range, 0-40%) and 15% (range, 0-25%) after three and four doses, respectively. After sequential doses, measurement of the time course of the effect of vecuronium yields pharmacokinetic and pharmacodynamic parameters with clinically acceptable accuracy in individual patients.