Population pharmacokinetic analysis of bupivacaïne used in regional anaesthesia

Abstract

Introduction The primary aim of this study was to establish the population pharmacokinetic (PPK) model of bupivacaine after combined lumbar plexus and sciatic nerve blocks and secondary aim is to assess the effect of patient's characteristics including age, body weight, sex and drugs co medication (Clonidine and Propofol) on pharmacokinetic parameters. Materials and method A total of 59 patients scheduled for elective lower extremity surgery with combined lumbar and sciatic nerve block using plain bupivacaine 0.5% were included. The total bupivacaine plasma concentrations were measured before injection and after two blocks placement and at selected time points. Monitoring of bupivacaine was made by high performance liquid chromatography (HPLC) with ultraviolet detection. Non-linear mixed effects modeling was used to analyze the PPK of bupivacaine. This pharmacokinetic model was validated using npde package for statistic software R. The simulations confirm that our final model was valid. Results and discussion Two compartment model with first order absorption, two input compartments, a central elimination and peripheral compartment was selected. The Shapiro-Wilks test of normality for normalized prediction distribution errors for this model ( P = 0.837) showed this as a valid model. The description of the quality of the estimate by the graphic diagnostic suggests a good fitting of the final model. The selected model predicts a population clearance of 503 mL/min (residual standard error [RSE] = 16.5%, 95% CI = [534.9–866.9]) with between subject variability of 93.16%. The central and peripheral volumes of distribution were respectively 6850 L and 120 L. The absorption of bupivacaine in two sites Ka1 and Ka2 were 0.00073/min for the lumbar site and 0.0037/min for the sciatic site. Within subject variability WSV% was 30, 3%. Drug Co medication, age, body weight and sex, have no effect on the bupivacaine pharmacokinetics in this studied population. Conclusion The developed model helps us to assess the systemic absorption of bupivacaine at two injections sites.