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

摘要

Abstract AimThe 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). MethodsThis 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. ResultsThe 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). ConclusionsAmisulpride 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.