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.
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Authors | Orit Cohen-Barak, Jacqueline Wildeman, Jeroen van de Wetering, Judith Hettinga, Petra Schuilenga-Hut, Aviva Gross, Shane Clark, Merav Bassan, Yossi Gilgun-Sherki, Boaz Mendzelevski, Ofer Spiegelstein |
Journal | Journal of clinical pharmacology
(J Clin Pharmacol)
Vol. 55
Issue 5
Pg. 573-83
(May 2015)
ISSN: 1552-4604 [Electronic] England |
PMID | 25524052
(Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Copyright | © 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology. |
Chemical References |
- Albumins
- Recombinant Fusion Proteins
- Recombinant Proteins
- TV-1380
- Butyrylcholinesterase
- Cocaine
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Topics |
- Adult
- Albumins
(adverse effects, pharmacokinetics, pharmacology)
- Area Under Curve
- Butyrylcholinesterase
(adverse effects, pharmacokinetics, pharmacology)
- Cocaine
(metabolism)
- Cocaine-Related Disorders
(drug therapy)
- Dose-Response Relationship, Drug
- Double-Blind Method
- Electrocardiography
- Female
- Half-Life
- Humans
- Injections, Intramuscular
- Male
- Maximum Tolerated Dose
- Metabolic Clearance Rate
- Recombinant Fusion Proteins
(adverse effects, pharmacokinetics, pharmacology)
- Recombinant Proteins
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