PHARMACOKINETIC ANALYSIS OF THE TIME-COURSE OF EFFECT OF ATRACURIUM

Objective: To examine the ability to determine clinically important pharmacokinetic and pharmacodynamic parameters of atracurium by the analysis of the time course of effect without the use of plasma concentration data. Design: Neuromuscular transmission was monitored with train-of-four stimulation and electromyographic quantitation of the first (T1) and fourth (T4) responses in eight anesthetized patients undergoing elective surgery. The time course of onset and recovery of neuromuscular blockade by three successive bolus doses of atracurium was recorded. Equations describing the theoretic time course of concentrations in the effect compartment and the dose-response relationship were fitted simultaneously to these data; the parameters of these equations derived from the fit of two doses were used to predict the response to a third dose. Fitting the equations to all three doses was also performed to assess the accuracy of predictions for atracurium. Results: From the depression of the first twitch after three consecutive doses in eight patients, the half-lives of uptake into and elimination from the effect compartment were 2.1 +/- 0.2 minutes (mean +/- SEM) and 25.8 +/- 2.3 minutes (n = 8). The doses producing 50% and 95% depression of the first twitch (ED(50) and ED(95)) were 168 +/- 15 and 280 +/- 25 mu g/kg, respectively, with a Hill coefficient of 6.1 +/- 0.5. The half-life of elimination estimated from the fourth twitch was similar to that from the first twitch. Conclusions: The analysis of high-resolution effect data is capable of giving pharmacokinetic and pharmacodynamic parameters with clinically acceptable accuracy within a short sampling time, without resorting to laboratory analysis. This method is specific for active drug and would be of value for individualization of administration for short-term treatment.