A pharmacokinetic-pharmacodynamic model for a muscle relaxant: Atracurium

Our goal was to develop a pharmacokinetic-pharmacodynamic model that describes the fate of atracurium and its metabolite laudanosine as well as the time course of the neuromuscular block. The model was based on the consideration of mass balance of atracurium and was constructed by postulating an effect compartment linked to the central compartment in the previously described open mammillary model for atracurium. The entry and exit rate constants, k(CE) and k(EC), were adjusted to satisfy the requirement that the peak amount in the effect compartment coincides with the peak submaximal block. We used previously published clinical data to arrive at the times to 50% neuromuscular block either during the onset of the block following an ED₅₀ dose or during the recovery following larger doses of atracurium. Laplace transforms were used to define the model, and the solution was obtained by iterative numeric adjustments of the rate constants. The model provides an excellent fit of the observed plasma concentrations of atracurium and laudanosine and simulates well the development and waning of the neuromuscular block. The model projects that the peak amount of atracurium in the effect compartment amounts to 14% of the injected dose and is reached at 7.6 min after the injection.