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.