TY - JOUR

T1 - Population pharmacokinetic-pharmacodynamic model of subcutaneous bupivacaine in a novel extended-release microparticle formulation

AU - Storgaard, Ida Klitzing

AU - Jensen, Elisabeth Kjær

AU - Bøgevig, Søren

AU - Balchen, Torben

AU - Springborg, Anders Holten

AU - Royal, Mike Allan

AU - Møller, Kirsten

AU - Werner, Mads Utke

AU - Lund, Trine Meldgaard

N1 - © 2024 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

U2 - 10.1111/bcpt.14004

DO - 10.1111/bcpt.14004

M3 - Journal article

C2 - 38504615

VL - 134

SP - 676

EP - 685

JO - Basic and Clinical Pharmacology and Toxicology

JF - Basic and Clinical Pharmacology and Toxicology

SN - 1742-7835

IS - 5

ER -