title: Assessment of Pharmacokinetic and Pharmacodynamic Interactions Between Albumin-Fused Mutated Butyrylcholinesterase and Intravenously Administered Cocaine in Recreational Cocaine Users.
abstract: Cocaine dependence presents a major public health issue, and to date, no pharmacotherapies are approved for its treatment. TV-1380 is a novel recombinant albumin-fused mutated butyrylcholinesterase (Albu-BChE) that has increased catalytic efficiency for cocaine compared with wild-type BChE and therefore has the potential to facilitate abstinence in cocaine-dependent subjects by decreasing exposure to cocaine and its reinforcing effects.
  
  
  METHODS
  This randomized, double-blind, placebo-controlled, parallel-group study in nondependent cocaine users was conducted to evaluate the effect of a single intramuscular dose of Albu-BChE (50, 100, and 300 mg) on the pharmacokinetic and metabolic profile of intravenous cocaine infusions (40 mg) administered at baseline and at 24, 96, and 168 hours after Albu-BChE dosing, to assess safety of coadministering Albu-BChE and cocaine, and to explore the subjective responses to cocaine infusions after Albu-BChE dosing.
  
  
  RESULTS
  Administration of Albu-BChE resulted in significant dose-dependent reductions in cocaine exposure (maximum concentration, area under the curve) and half-life. Effects were greatest at 24 hours after Albu-BChE dose, but were sustained up to 168 hours. Spearman correlations indicated a significant negative relationship between Albu-BChE concentration and cocaine clearance and exposure. Consistent with its mechanism of action, Albu-BChE also shifted cocaine metabolism toward preferential formation of ecgonine methyl ester. Administration of Albu-BChE was associated with modest decreases in subjective reports of feeling high and willingness to take cocaine again after cocaine infusion. Coadministration of Albu-BChE and cocaine was safe and well tolerated.
  
  
  CONCLUSIONS
  Administration of Albu-BChE at single doses of 50, 100, and 300 mg safely resulted in long-lasting decreases in cocaine exposure in recreational cocaine users.
authors.affiliation: From the *Altreos Research Partners, Inc and †Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; ‡Research and Development, Teva Pharmaceuticals, Netanya, Israel; and §Algorithme Pharma, Laval, Québec; and ∥DL Global Partners Inc and ¶Biopharma Services Inc, Toronto, Ontario, Canada.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Shram
authors.forename: Orit
authors.initials: O
authors.lastname: Cohen-Barak
authors.forename: Bijan
authors.initials: B
authors.lastname: Chakraborty
authors.forename: Merav
authors.initials: M
authors.lastname: Bassan
authors.forename: Kerri A
authors.initials: KA
authors.lastname: Schoedel
authors.forename: Hussein
authors.initials: H
authors.lastname: Hallak
authors.forename: Eli
authors.initials: E
authors.lastname: Eyal
authors.forename: Sivan
authors.initials: S
authors.lastname: Weiss
authors.forename: Yossi
authors.initials: Y
authors.lastname: Gilgun-Serki
authors.forename: Yossi
authors.initials: Y
authors.lastname: Gilgun
authors.forename: Edward M
authors.initials: EM
authors.lastname: Sellers
authors.forename: Janice
authors.initials: J
authors.lastname: Faulknor
authors.forename: Ofer
authors.initials: O
authors.lastname: Spiegelstein
mesh_terms: D000293:Adolescent; D000328:Adult; D000418:Albumins / Q000008:administration & dosage* / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000008:administration & dosage* / Q000097:blood*; D003042:Cocaine / Q000008:administration & dosage* / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006801:Humans; D013287:Illicit Drugs / Q000097:blood*; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000418:Albumins; D013287:Illicit Drugs; D002091:Butyrylcholinesterase; D003042:Cocaine