Tradipitant: A Novel Neurokinin-1 Receptor Antagonist for Motion Sickness.

Abstract

Background: Motion sickness affects millions of people with common symptoms, including nausea and vomiting. Medications used for management of motion sickness since 1870 predominately have anticholinergics and antihistamines properties. For the past 40 years, there have been no advances in medication options for motion sickness until recently, a novel agent, tradipidant received the Food and Drug Administration approval for symptoms related to motion sickness.

Mechanism of action, pharmacodynamics, and pharmacokinetics: Tradipitant is a selective neurokinin-1 (NK-1) receptor antagonist, blocking the actions of substance P, a neurotransmitter from the tachykinin family. It has high affinity for NK-1 receptors that are present throughout the emetic pathway. The 4 major metabolites of this drug (ie, M2, M3, M4, and M8) have shown a similar affinity to the NK-1 receptor as the parent drug. Pharmacokinetic data have revealed that tradipitant absorption is delayed when administered with food. The volume of distribution is 1956 L and is highly plasma protein bound (∼96%). The half-life is 34 hours. Tradipitant is predominately metabolized by CYP450-mediated pathways and through glucuronidation. Approximately 80% of excretion of tradipitant occurs in the feces.

Clinical trials: Two phase 3 pivotal trials, Motion Syros (N = 365) and Motion Serifos (N = 316), randomized, double-blinded, placebo-controled, showed significant efficacy for tradipitant in preventing vomiting associated with motion sickness. In Motion Syros, tradipitant groups experienced significantly lower incidences of vomiting than placebo (170 mg tradipitant = 18.3%, 85 mg tradipitant = 19.5%, placebo = 44.3%). In Motion Serifos, 10.4% of the 170-mg tradipitant group and 18.3% of the 85-mg tradipitant group experienced vomiting, compared with 37.7% of the placebo group ( P = 0.00002 and P = 0.0014, respectively). The results of the 2 trials validated tradipitant as an effective NK-1 receptor antagonist for motion sickness prevention. The drug was well tolerated with a favorable safety profile and no serious adverse events.

Therapeutic advance: Tradipitant works by blocking the NK-1 receptors found in the emetic pathway and it has been proven in pivotal trials effective for prevention of vomiting due to motion sickness. It reduces motion sickness symptoms in 2 phase 3 trials and offers a revolutionary new treatment option for people who experience motion sickness.