Dose safety and pharmacodynamics of subcutaneous bupivacaine in a novel extended‐release microparticle formulation: A phase 1, dose‐ascending study in male volunteers

Abstract

A novel microparticle‐based extended‐release local anaesthetic containing a bupivacaine/poly‐lactic‐co‐glycolic acid (PLGA; LIQ865A) or plain bupivacaine (LIQ865B) was examined in a first‐in‐human trial. The objectives were to examine the dose safety/tolerability and pharmacodynamics. Randomized subcutaneous injections of LIQ865A (n = 16) or LIQ865B (n = 12) and diluent, contralaterally, were administered in a dose‐ascending manner (150‐ to 600‐mg bupivacaine). Subjects were admitted 24 h post‐injection and followed for 30 days post‐injection. The risk ratios (RRs; 95% CI) of erythematous reactions for LIQ865A versus diluent was 9.00 (1.81–52.23; P = 0.006) and for LIQ865B versus diluent 2.50 (0.69–9.94; P = 0.37). The RR for the development of hematomas (LIQ865A versus diluent) were 3.25 (1.52–8.16; P = 0.004) and 4.00 (0.72–24.89; P = 0.32) (LIQ865B versus diluent). Subcutaneous indurations persisting for 4–13 weeks were seen in 6/16 subjects receiving LIQ865A. One subject receiving LIQ865A (600‐mg bupivacaine) developed intermittent central nervous system (CNS) symptoms of local anaesthetic systemic toxicity (85 min to 51 h post‐injection) coinciding with plasma peak bupivacaine concentrations (490–533 ng/ml). Both LIQ865 formulations demonstrated dose‐dependent hypoesthesia and hypoalgesia. The duration of analgesia ranged between 37 and 86 h. The overall number of local adverse events, however, prohibits clinical application without further pharmacological modifications.