Safety, pharmacokinetics, and pharmacodynamics of TV‐1380, a novel mutated butyrylcholinesterase treatment for cocaine addiction, after single and multiple intramuscular injections in healthy subjects

Abstract

Human plasma butyrylcholinesterase (BChE) contributes to cocaine metabolism and has been considered for use in treating cocaine addiction and cocaine overdose. TV-1380 is a recombinant protein composed of the mature form of human serum albumin fused at its amino terminus to the carboxy-terminus of a truncated and mutated BChE. In preclinical studies, TV-1380 has been shown to rapidly eliminate cocaine in the plasma thus forestalling entry of cocaine into the brain and heart. Two randomized, blinded phase I studies were conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of TV-1380, following single and multiple administration in healthy subjects. TV-1380 was found to be safe and well tolerated with a long half-life (43–77 hours) and showed a dose-proportional increase in systemic exposure. Consistent with preclinical results, the ex vivo cocaine hydrolysis, TV-1380 activity clearly increased upon treatment in a dose-dependent manner. In addition, there was a direct relationship between ex vivo cocaine hydrolysis (kel) and TV-1380 serum concentrations. There was no evidence that TV-1380 affected heart rate, the uncorrected QT interval, or the heart-rate-corrected QTcF interval. TV-1380, therefore, offers a safe once-weekly therapy to increase cocaine hydrolysis.

Biologics to treat substance use disorders: Current status and new directions

“…9,18 Cocaine-degrading enzymes derived from human plasma butyrylcholinesterases (BChE) and bacterial cocaine esterases (CocE) have been tested for treatment of cocaine dependence and overdose (NCT01887366, and NCT01846681, Table 1). [148][149][150] These clinical studies showed no evidence of side effects, and provide proof of concept for enzyme-based SUD treatments. A detailed review of clinical studies of cocaine esterases can be found elsewhere.…”

Benzoic acid is not the only important product of accelerated metabolism of cocaine

“…This work is exciting to those involved in pharmacokinetic approaches to drug toxicity; such constructs promise to be the first drug-metabolizing enzymes used as therapeutic agents. The analog described (1) seems to be the third of its type; this analog is apparently the longest lasting in the series (2,3).…”

Potential anti-obesity effects of a long-acting cocaine hydrolase

“…CocH2 and CocH3 etc . were designed in our lab to improve the catalytic efficiency of human BChE against cocaine for treatment of cocaine addiction and overdose [23, 26–32], and were not expected to improve the catalytic efficiency against ghrelin. Hence, it is not surprizing to know that CocH3 has a moderate catalytic efficiency ( k cat / K m = 4.8 × 10 5 min −1 M −1 ) against ghrelin compared to that ( k cat / K m = 6.1 × 10 5 min −1 M −1 ) of wild-type human BChE, and that CocH2 has a slightly lower catalytic efficiency ( k cat / K m = 2.2 × 10 5 min −1 M −1 ) against ghrelin [33].…”