Objective: To characterize the effect of therapeutic and supratherapeutic doses of ampreloxetine on cardiac repolarization in healthy subjects.

Background: Ampreloxetine is a potent NE reuptake inhibitor with selectivity for inhibiting uptake of NE versus serotonin. Results of a Phase 3 clinical trial evaluating ampreloxetine for treatment of nOH showed that MSA patients achieved clinically meaningful and durable symptom improvement over 22 weeks.  In clinical trials to date, there have been no reported ECG findings or QT prolongation of clinical significance, nor any incidences of seizures or Torsades de Pointes at ampreloxetine doses ranging from 2 to 50 mg. This thorough QT study was conducted to evaluate the potential for corrected QT interval (QTc) changes after administration of therapeutic (10 mg QD) and supratherapeutic (40 mg QD) ampreloxetine doses.

Method: This single-center, randomized, double-blind, placebo-controlled, positive-controlled, multiple dose, parallel group study was conducted in 72 healthy subjects. Continuous digital ECGs, extracted using expert precision QT analysis, and pharmacokinetic assessments were used to model the relationship between plasma ampreloxetine concentrations and change-from-baseline (∆) QTc.

Results: Due to the observed effect of ampreloxetine on heart rate (approximately 8 to 13 bpm at 40 mg QD), multiple QT correction methods were compared. Heart rate dependency of QTc was best removed by QTcS. Ampreloxetine’s effect on QTcS interval was small and not dose-dependent, with least squares mean placebo corrected change from baseline (∆∆) QTcS varying between 2.1 and 7.7 ms after 40 mg QD. The slope of the concentration-QTcS relationship was not statistically different from zero (0.010 ms per ng/mL; 90% CI: -0.0133 to 0.0341). The predicted mean effect of ampreloxetine on ΔΔQTcS at clinically relevant therapeutic (10 mg QD; mean Cmax: 16.5 ng/mL) and supratherapeutic (40 mg QD; mean Cmax: 94.3 ng/mL) plasma ampreloxetine exposures was 3.2 ms (90% CI: 1.29 to 5.19 ms) and 4.1 ms (90% CI: 1.20 to 6.90 ms), respectively, below the regulatory threshold of concern (10 ms).

Conclusion: Ampreloxetine did not prolong the QTc interval at therapeutic or supratherapeutic dose levels to any clinically relevant extent.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-multiple-dose-thorough-qt-study-to-evaluate-the-effect-of-ampreloxetine-on-cardiac-repolarization-in-healthy-subjects/