Phase 1 single-centre, placebo and levobupivacaine controlled study in healthy volunteers to assess the safety, tolerability, efficacy, and pharmacokinetics of LL10, a novel long-acting local anaesthetic.

Abstract

LL10 is a novel long-acting local anaesthetic composed of QX-OH 1.26% and levobupivacaine hydrochloride 0.325%. This first-in-human trial assessed the safety, tolerability, efficacy, and pharmacokinetic profile of LL10. We investigated three administration routes: s.c. infiltration, femoral nerve block (FNB), and transversus abdominis plane block (TAPB), with levobupivacaine as a positive control (n=18 total, six per route). For s.c. infiltration, 40 subjects received concentration escalation of LL10 (4 ml, seven cohorts); for FNB, 30 received LL10 at escalating concentrations (20 ml, six cohorts); and for TAPB, 49 received 1.26%/0.325% LL10 at escalating volumes (25-55 ml, seven cohorts). Each LL10 cohort included a placebo control (n=20). Safety evaluations included vital signs, adverse events (AEs), physical examinations, and laboratory tests. Sensory block was evaluated using pinprick, mechanical pain thresholds, and transcutaneous electrical stimulation. Motor block was evaluated via lower limb muscle strength grading. Plasma pharmacokinetics of QX-OH and levobupivacaine were investigated. None of the 137 enrolled subjects developed severe AEs. Dose-dependent systemic AEs including dizziness, perioral and tongue numbness, and cardiovascular symptoms were observed after TAPB; all resolved spontaneously. LL10 showed linear pharmacokinetics. The 1.26%/0.325% LL10 demonstrated prolonged FNB duration compared with levobupivacaine 0.325% (median, 25.0 [21.8-29.5] h vs 15.5 [6.0-21.2] h; P = 0.021). The 1.26%/0.325% LL10 was tolerated in healthy volunteers at doses up to 40 ml (equivalent to 7/1.81 mg kg^-1). LL10 produced prolonged local anaesthesia in FNB compared with levobupivacaine 0.325%, but not in s.c. infiltration or transversus abdominus plane block. ChiCTR2200064437 (Chinese Clinical Trial Registry).