Thorough QT study of the effect of intravenous amisulpride on QTc interval in Caucasian and Japanese healthy subjects.

Abstract

AIM:

The D2 /D3 antagonist amisulpride has shown promising efficacy against postoperative nausea and vomiting (PONV) at low doses. We investigated whether intravenous amisulpride has an effect on the QTc interval in a formal Thorough QT study (TQT).

METHODS:

This was a randomized, double-blind, placebo and positive-controlled, four-way crossover study. Forty healthy Caucasian and Japanese subjects were included to receive a single administration of 5 mg and 40 mg of i.v. amisulpride or a single oral dose of moxifloxacin or placebo per period.

RESULTS:

The therapeutic dose of 5 mg amisulpride was associated with a slight, transient increase in mean ΔΔQTcF, from 2.0 ms prior to dosing to a peak of 5 ms (90% CI: 2.8, 7.1 ms) at 8 min, decreasing to 2.1 ms at 30 min after dosing. The supra-therapeutic dose of 40 mg given at twice the infusion rate was associated with prolongation in ΔΔQTcF peaking at 23.4 ms (90% CI: 21.3, 25.5 ms) at the end of infusion (8 min), returning below 10 ms within 1.5 h. Assay sensitivity was confirmed; ΔΔQTcF had increased by 12.3 ms (90% CI 10.1, 14.6 ms) at 4 h post-dose. The PK-PD relationship revealed no differences between Caucasian and Japanese subjects (p-value > 0.5).

CONCLUSIONS:

Amisulpride has a plasma concentration-dependent effect on the QTc interval. The proposed therapeutic dose for management of PONV does not lead to a prolongation of QTcF above the threshold of regulatory concern, while such effect could not be excluded for the supratherapeutic dose.

• Authors: Jörg Täubel, Georg Ferber, Gabriel Fox, Sara Fernandes, Ulrike Lorch, A John Camm
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 83 Issue 2 Pg. 339-348 (02 2017) ISSN: 1365-2125 [Electronic] England
• PMID: 27618796 (Publication Type: Comparative Study, Journal Article, Randomized Controlled Trial)
• Copyright: © 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Chemical References

• Dopamine Antagonists
• Fluoroquinolones
• Sulpiride
• Amisulpride
• Moxifloxacin

Topics

• Administration, Intravenous
• Adult
• Amisulpride
• Asian People
• Cross-Over Studies
• Dopamine Antagonists (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Electrocardiography
• Female
• Fluoroquinolones (administration & dosage, adverse effects)
• Humans
• Long QT Syndrome (chemically induced)
• Male
• Middle Aged
• Moxifloxacin
• Sulpiride (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• White People
• Young Adult