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Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600\u2009mg in a phase 1 randomized, placebo\u2010controlled, double\u2010blind, dose\u2010ascending study with two different microparticle formulations, LIQ865A and LIQ865B. Warmth detection threshold was used as a surrogate pharmacodynamic endpoint. Population pharmacokinetic\u2013pharmacodynamic models were fitted to plasma concentration\u2010effect\u2010time data using non\u2010linear mixed\u2010effects modelling. The pharmacokinetics were best described by a two\u2010compartment model with biphasic absorption as two parallel absorption processes: a fast, zero\u2010order process and a slower, first\u2010order process with two transit compartments. The slow absorption process was found to be dose\u2010dependent and rate\u2010limiting 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\u2013pharmacodynamic 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.<\/jats:p>","DOI":"10.1111\/bcpt.14004","type":"journal-article","created":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T07:23:53Z","timestamp":1710919433000},"page":"676-685","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Population pharmacokinetic\u2013pharmacodynamic model of subcutaneous bupivacaine in a novel extended\u2010release microparticle formulation"],"prefix":"10.1111","volume":"134","author":[{"given":"Ida Klitzing","family":"Storgaard","sequence":"first","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth 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