Ida Klitzing Storgaard (1), Elisabeth Kjær Jensen (2,3), Mads Utke Werner (2,3,4), and Trine Meldgaard Lund (1)
(1) Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DENMARK, (2) Department of Anesthesia, Pain and Respiratory Support, Neuroscience Center, Rigshospitalet, DENMARK, (3) DanTrials, Zelo Phase 1 Unit, Copenhagen University Hospitals, DENMARK, (4) Department of Clinical Science, Lund University Lund, SWEDEN
Introduction and Objectives: Improving postoperative pain management is essential to ensure better medical outcomes after surgical procedures [1]. Using local anesthetics such as bupivacaine in interventional pain management is generally considered preferable to systemically administered opioids, but most local anesthetics for postoperative interventional pain management have a duration of efficacy of less than 24 hours [1,2,3]. Previously developed popPK and/or pharmacodynamic (PD) models of bupivacaine were based on central neuraxial blocks [4-7]. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic model of subcutaneously administered bupivacaine in a novel microparticle formulation for extended release.
Methods: Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects (required age 18-45 years; BMI 18.5-30.0 kg/m2; weight >60 kg) in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study. Diluent was administered in the other leg as control and baseline for pharmacodynamic measurements. The extended-release formulations were made using the PRINT®-technology, producing hexagonal microparticles [8]. Formulation LIQ865A consisted of a mix of the PRINT® bupivacaine base and poly-lactic-co-glycolic acid in a ratio of 55%/45%, while formulation LIQ865B consisted of 100% PRINT® bupivacaine base. Warmth detection threshold (WDT) measurement was used as a surrogate PD endpoint. The temperature on the skin test areas was increased using a ramp rate of 1°C/s until a sensation of warmth was perceived, with a cut-off limit of 50°C to avoid skin damage. Plasma concentration-effect-time data were fitted to population pharmacokinetic-pharmacodynamic models using non-linear mixed-effects modeling.
Results: The pharmacokinetics of LIQ865 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. Large inter-individual variability was found for parameters relating to both absorption processes. The slow absorption process was found to be dose-dependent and rate-limiting for bupivacaine clearance at higher doses. Apparent bupivacaine clearance for the lowest dose of 150 mg was estimated to 35.4 L/h (CV = 6.3%, IIV = 24.5%), which is similar to previous studies [2]. The apparent clearance and the transit rate constant (0.117 h-1, CV = 13%, IIV = 31.2%) describing the slow absorption process both decreased with increasing doses following a power function with a shared covariate effect of dose normalized to the lowest dose of 150 mg (assuming no to neglectable covariate effect at this dose) on the two parameters. The covariate effect was estimated to -0.43 (CV = 24%). The pharmacokinetic-pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function with a slope of 0.042 °C∙L∙µg-1 (CV = 13%, IIV = 56.7%) and an intercept/baseline of 36.7°C (CV = 0.5%). Formulation type (A or B) did not significantly affect any model parameters.
Conclusions: The biphasic absorption was generally well-described for individuals and the population as two parallel processes. Apparent bupivacaine clearance and the transit rate constant describing the slow absorption process both decreased with increasing doses following a power function. A linear function best described the relationship between plasma concentrations and effect. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine, and the biphasic absorption seen for several local anesthetics.
*Submitted manuscript based on the same work: Population pharmacokinetic-pharmacodynamic model of subcutaneous bupivacaine in a novel extended-release microparticle formulation. Ida Klitzing Storgaard, Elisabeth Kjær Jensen, Søren Bøgevig, Torben Balchen, Anders Holten Springborg, Mike Allan Royal, Kirsten Møller, Mads Utke Werner, and Trine Meldgaard Lund (under revision at BCPT at the time of abstract submission)
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Reference: PAGE 32 (2024) Abstr 10766 [www.page-meeting.org/?abstract=10766]
Poster: Drug/Disease Modelling - Other Topics