title: 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.
authors.affiliation: Teva Pharmaceuticals, Inc., Netanya, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Cohen-Barak
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Wildeman
authors.forename: Jeroen
authors.initials: J
authors.lastname: van de Wetering
authors.forename: Judith
authors.initials: J
authors.lastname: Hettinga
authors.forename: Petra
authors.initials: P
authors.lastname: Schuilenga-Hut
authors.forename: Aviva
authors.initials: A
authors.lastname: Gross
authors.forename: Shane
authors.initials: S
authors.lastname: Clark
authors.forename: Merav
authors.initials: M
authors.lastname: Bassan
authors.forename: Yossi
authors.initials: Y
authors.lastname: Gilgun-Sherki
authors.forename: Boaz
authors.initials: B
authors.lastname: Mendzelevski
authors.forename: Ofer
authors.initials: O
authors.lastname: Spiegelstein
mesh_terms: D000328:Adult; D000418:Albumins / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002091:Butyrylcholinesterase / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003042:Cocaine / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D006207:Half-Life; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D011993:Recombinant Fusion Proteins / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011994:Recombinant Proteins
chemical_list: D000418:Albumins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C000604228:TV-1380; D002091:Butyrylcholinesterase; D003042:Cocaine
keywords: TV-1380; butyrylcholinesterase; cocaine; healthy volunteers; pharmacokinetics; safety; tolerability