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αO-conotoxin GeXIVA[1,2] was isolated in our laboratory from Conus generalis  , a snail native to the South China Sea, and is a novel, nonaddictive, intramuscularly administered analgesic targeting the α9α10 nicotinic acetylcholine receptor (nAChR) with an IC 50 of 4.61 nM. However, its pharmacokinetics and related mechanisms underlying the analgesic effect remain unknown. Herein, pharmacokinetics and multiscale pharmacokinetic modelling in animals were subjected systematically to mechanistic assessment for αO-conotoxin GeXIVA[1,2]. The intramuscular bioavailability in rats and dogs was 11.47% and 13.37%, respectively. The plasma exposure of GeXIVA[1,2] increased proportionally with the experimental dose. The plasma protein binding of GeXIVA[1,2] differed between the tested animal species. The one-compartment model with the first-order absorption population pharmacokinetics model predicted doses for humans with bodyweight as the covariant. The pharmacokinetics-pharmacodynamics relationships were characterized using an inhibitory loss indirect response model with an effect compartment. Model simulations have provided potential mechanistic insights into the analgesic effects of GeXIVA[1,2] by inhibiting certain endogenous substances, which may be a key biomarker. This report is the first concerning the pharmacokinetics of GeXIVA[1,2] and its potential analgesic mechanisms based on a top-down modelling approach.

Novel αO-conotoxin GeXIVA[1,2] Nonaddictive Analgesic with Pharmacokinetic Modelling-Based Mechanistic Assessment