Peripheral link model as an alternative for pharmacokinetic-pharmacodynamic modeling of drugs having a very short elimination half-life

Attempts to obtain estimates of pharmacokinetic-pharmacodynamic (PK-PD) par ameters for mivacurium with traditional central link models were unsuccessf ul in many patients. We hypothesized that a link model with the peripheral compartment would be more appropriate for mivacurium in view of its extreme ly rapid plasma clearance and its potential elimination by tissue pseudocho linesterases. For validation purposes, the peripheral link model was applie d to other neuromuscular blocking agents (NMBA), i.e., atracurium and doxac urium which have respectively an intermediate and a long elimination half-l ife. Assuming peripheral elimination in PK-PD modeling was investigated but found to have no impact on the estimation of PK-PD parameters. Our results indicate that, for drugs having intermediate and long elimination half-liv es, EC50 values are similar with either the central or peripheral link mode l. For mivacurium, a peripheral link model enables PK-PD modeling in all su bjects, with more precision in the PK-PD parameter estimates and a better f itting of the effect data when compared to the central link model. For thes e reasons, a peripheral link model should be preferred for mivacurium.