Pharmacokinetic-pharmacodynamic modeling of doxacurium: effect of input rate

One of the basic assumptions in pharmacokinetic-pharmacodynamic modeling (PK-PD) is that drug equilibration rate constant between plasma concentration and effect (Ke0) is not changed by input rate. To test this assumption in a clinical setting, a 25 micrograms/kg i.v. dose of doxacurium was administered either by bolus injection or 10-min infusion to 15 anesthetized patients. Neuro-muscular function was monitored using train-of-four stimulation of the ulnar nerve. For the short infusion dose, arterial concentrations were measured at I-min intervals during infusion and at frequent intervals thereafter. Following the iv bolus dose, the early PK profile of doxacurium was investigated by measuring doxacurium arterial concentrations every 10 sec during the first 2 min and at frequent intervals thereafter. PK-PD modeling was performed using nonparametric approach with and without including a finite receptor concentration (Rtot) in the effect compartment. Kinetic parameters were unchanged. For the bolus and the infusion, Ke0 values were 0.053 +/- 0.006 and 0.056 +/- 0.009 min-1, respectively. Using the Rtot model, corresponding Ke0 values were 0.148 +/- 0.016 and 0.150 +/- 0.024, respectively. The relatively faster Ke0 obtained with the Rtot model is compatible with the high potency of doxacurium. Our results show that PK-PD parameters derived with either a bolus or an infusion mode of administration are equally reliable.