Population pharmacokinetic-pharmacodynamic model of subcutaneous bupivacaine in a novel extended-release microparticle formulation

The objective of this study was to develop a population pharmacokinetic-pharmacodynamic model of subcutaneously administered bupivacaine in a novel extended-release microparticle formulation for postoperative pain management. Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study with two different microparticle formulations, LIQ865A and LIQ865B. Warmth detection threshold was used as a surrogate pharmacodynamic endpoint. Population pharmacokinetic-pharmacodynamic models were fitted to plasma concentration-effect-time data using non-linear mixed-effects modelling. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The slow absorption process was found to be dose-dependent and rate-limiting for elimination at higher doses. Apparent bupivacaine clearance and the transit rate constant describing the slow absorption process both appeared to decrease with increasing doses following a power function with a shared covariate effect. The pharmacokinetic-pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine and the biphasic absorption seen for several local anaesthetics. The population pharmacokinetics and pharmacodynamics of a novel extended-release microparticle-based formulation of the local anaesthetic bupivacaine were examined in a phase one trial. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The warmth detection threshold was used as a surrogate pharmacodynamic endpoint, and the pharmacokinetic-pharmacodynamic relationship between plasma concentrations and the effect was best described by a linear function. image