The pharmacokinetics of lignocaine in humans during a computer‐controlled infusion

Abstract

Several types of chronic pain syndromes are effectively treated with sodium channel blockers such as lignocaine. Further investigation of this therapeutic modality would be facilitated by refinement of the parameters describing lignocaine distribution and elimination. This would allow precise lignocaine infusion by a computer‐controlled infusion to attain and maintain stable target lignocaine concentrations. Arterial blood samples were obtained at frequent intervals during a computer‐controlled infusion of lignocaine in 12 adult human volunteers. Plasma lignocaine concentrations of 1, 2, 3, 4 and 5μg/ml were targeted for 15 min at each concentration. A three‐compartment mammillary pharmacokinetic model best described the resulting concentration vs time profile. A population pharmacokinetic analysis was performed using three different techniques; the two‐stage, pooled and mixed effects modelling. There was marked overshoot of the plasma concentration above the target prior to refinement of the pharmacokinetic parameters. The best parameters of a three‐compartment mammillary model fit to the measured concentration using the pooled data approach were: V₁ = 7.44, V₂ =11.5 and V₃ = 97.71; Cl₁ = 0.585, Cl₂ = 2.23 and Cl₃ =1.64 Umin. Similarly calculated parameters using NONMEM were V₁ = 6.99, V₂ =12.2 and V₃ =1341; Cl₁ = 0.703, Cl₂ =1.24 and Cl₃ =1.49 Umin. The addition of age as a covariate of the pharmacokinetic parameters improved the model in both cases. Height, lean body mass and body surface area as covariates of the pharmacokinetic parameters did not improve the predicted value of the model. Prospective testing of the pharmacokinetic parameters will be required to define whether they function well. The refinement of pharmacokinetic parameters for the computer‐controlled intravenous infusion of lignocaine will facilitate further research in pain therapy. Published lignocaine pharmacokinetic values have a relatively large central volume of distribution, and hence, when implemented as a computer‐controlled infusion, result in dramatic overshoot shortly after targeting a higher plasma concentration. In light of the long‐lasting pain relief provided by sodium channel blockade in neuropathic pain states, overshoot of plasma concentrations must be avoided if the concentration vs effect relationship is to be defined.