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

AIM: The D(2)/D(3) 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.