TV-1380 attenuates cocaine-induced changes in cardiodynamic parameters in monkeys and reduces the formation of cocaethylene

•TV-1380 is mutated human BChE that has high enzymatic activity against cocaine.•TV-1380 in monkeys up to 50 mg/kg twice weekly for 13 weeks was well tolerated.•TV-1380 changed the metabolic fate of cocaine and the ratio between its metabolites.•TV-1380 treatment prior to cocaine significantly reduced cardiac effects of cocaine.•TV-1380 reduced plasma levels of the toxic metabolite cocethylene. TV-1380 is a rationally mutated, human BChE fused to human serum albumin that has high hydrolytic enzymatic activity against cocaine and as well as an extended elimination half-life. The present studies examined the safety of TV-1380 and its protective effect when given to monkeys alone or concomitantly with cocaine and ethanol. A set of studies was conducted in monkeys with TV-1380. The parameters tested included telemetric assessment of cardiovascular parameters, clinical pathology, plasma analysis of cardiac troponin I, ex-vivo analyses of cocaethylene and PK analysis of serum concentrations of TV-1380, cocaine and its metabolites, and histopathological examinations. TV-1380 treatment in monkeys was well tolerated. TV-1380 pretreatment prior to cocaine significantly attenuated the cardiac effects of cocaine and reduced cocaine-induced elevations in serum cardiac troponin I. TV-1380 changed the metabolic fate of cocaine resulting in decreased exposure to benzoylecgonine, while increasing the exposure to ecgonine methyl ester in plasma.TV-1380 reduced the plasma levels of the toxic metabolite cocaethylene formed after co-administration of ethanol and cocaine. The results of this study demonstrate that TV-1380 not only accelerates the elimination of cocaine, but also protects the treated animal from the cardiac effects of cocaine, and inhibits the formation of the toxic cocaethylene metabolite when cocaine is given together with ethanol, supporting further clinical development of modified BChE products as possible treatments for cocaine abuse.