Safety, pharmacokinetics, and pharmacodynamics of TV-1380, a novel mutated butyrylcholinesterase treatment for cocaine addiction, after single and multiple intramuscular injections in healthy subjects.
Bottom Line: 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.There was no evidence that TV-1380 affected heart rate, the uncorrected QT interval, or the heart-rate-corrected QTcF interval.
Affiliation: Teva Pharmaceuticals, Inc., Netanya, Israel.Show MeSH
Related in: MedlinePlus
Mentions: Subjects were admitted to the clinical center on Day −1, the day before dosing and baseline measures of vital signs, ECG, urine drug screen, blood tests, laboratory, and neurological assessments were conducted. In the SAD study (Figure 1a), subjects were randomly assigned to 1 of 7 dose groups (0.5, 1.5, 5, 15, 50, 150, and 300 mg) and received TV-1380 (n = 6 per dose) or placebo (n = 2 per dose) by intramuscular (IM) injection. Subjects received single IM injections in volumes ranging from 0.5 to 5 mL for TV-1380 doses 0.5–150 mg and respective placebo groups; and received 2 IM injections, each a volume of 5 mL for the TV-1380 300 mg dose and respective placebo. The IM injections of TV-1380 and placebo occurred in the buttock (maximus gluteus muscle; for 1 injection into the left aspect and for 2 injections in the left and right aspects of the buttocks). A starting dose of 0.5 mg was selected on the basis of the minimal pharmacologically active dose (PAD) in Cynomolgus monkeys (0.2 mg/kg). The human equivalent dose (HED) of the PAD is 4.5 mg in a 70 kg individual. The proposed starting dose, therefore, was about 10 times lower than the HED of the PAD. A starting dose of 0.5 mg was also about 200 times lower than the NOEL in rats (9 mg/kg in rats) and 600 times lower than the NOEL in Cynomolgus monkeys (15 mg/kg), on an HED basis. There was an interval of at least 7 days between any 2 consecutive dose levels and doses were escalated only after a favorable safety review of the previous dose. Subjects remained in the clinic until the morning of Day 4 (72 hours postdosing) and thereafter returned for follow-up visits up to Day 35 (816 hours postdosing).