A Randomized, Double‐Blind, Placebo‐ and Positive‐Controlled, 4‐Period Crossover Study of the Effects of Solriamfetol on QTcF Intervals in Healthy Participants

Abstract

Solriamfetol, a dopamine and norepinephrine reuptake inhibitor, is approved (United States and European Union; Sunosi) to treat excessive daytime sleepiness associated with narcolepsy (75-150 mg/day) or obstructive sleep apnea (37.5-150 mg/day). A thorough QT/QTc study assessed solriamfetol effects on QT interval (Fridericia correction for heart rate; QTcF). This randomized, double-blind, placebo-and positive-controlled, 4-period crossover study compared single doses of 300 and 900 mg solriamfetol, 400 mg moxifloxacin, and placebo in healthy adults. Placebo-and predose-adjusted mean differences in QTcF (ddQTcF; primary end point) were analyzed, and solriamfetol pharmacokinetics were characterized. Fifty-five participants completed all periods. Upper bounds of 2-sided 90% confidence intervals (CIs) for ddQTcF for both solriamfetol doses were <10 milliseconds at all postdose time points. Assay sensitivity was demonstrated with moxifloxacin; lower bounds of 2-sided 90%CIs for ddQTcF > 5 milliseconds at 1, 2, and 3 hours postdose. There were no QTcF increases > 60 milliseconds or QTcF values > 480 milliseconds at either solriamfetol dose. Solriamfetol median t max was 2-3 hours; exposure was dose-proportional. More participants experienced adverse events (AEs) after solriamfetol 900 versus 300 mg (70% vs 29%); none were serious (all mild/moderate), and there were no deaths. Common AEs were nausea, dizziness, and palpitations. Neither solriamfetol dose resulted in QTcF prolongation > 10 milliseconds.

Profile of Solriamfetol in the Management of Excessive Daytime Sleepiness Associated with Narcolepsy or Obstructive Sleep Apnea: Focus on Patient Selection and Perspectives

“…23 In a randomized, double-blind, fourperiod, placebo-and positive-controlled crossover study, the effects of solriamfetol 300 mg and 900 mg on QTc interval were studied and demonstrated minimal risk of QTc prolongation. 50 The FDA's review of this study concluded that a dose of 300 mg of solriamfetol (which is twice the highest FDA-approved dose) did not prolong the corrected QT interval by Fredericia (QTcF) to a clinically relevant extent. 1 There were no deaths with solriamfetol use in the 12week trials (TONES 2 and 3).…”

Solriamfetol for the Management of Excessive Daytime Sleepiness

“…15 Similar to findings with other wake promoting agents, cardiovascular safety reports have noted dose-dependent increases in blood pressure and heart rate with solriamfetol. Solriamfetol did not increase the QTcF interval > 10 ms in a study with healthy subjects at doses of 300 mg and 900 mg. 32 Secondary to the possible comorbidities present in individuals with OSA, a lower initial dose and frequent evaluation is warranted to minimize risk of major cardiovascular events. In the TONES 5 study, worsening of heart rate or blood pressure was not observed over 52 weeks.…”