Gastroparesis is a chronic neuromuscular disorder of the upper gastrointestinal tract in which episodic exacerbation can lead to frequent hospitalizations and severe disability.
Dopamine D2 /D3 receptor antagonists have been used to treat patients with
gastroparesis with some efficacy; however, their chronic use is limited owing to associated central nervous system (CNS) or cardiovascular safety concerns.
Trazpiroben (TAK-906) is a
dopamine D2 /D3 receptor antagonist under development for the long-term treatment of
gastroparesis. Preclinical studies in rat and dog have shown
trazpiroben to have minimal brain penetration and low affinity for the human
ether-à-go-go-related gene (hERG)
potassium channel (IC50 , 15.6 µM), thereby reducing the risk of the CNS and cardiovascular adverse effects seen with other
dopamine D2 /D3 receptor antagonists. This phase 1 trial evaluated the safety, pharmacokinetics, and pharmacodynamics of
trazpiroben in healthy participants.
Trazpiroben was rapidly absorbed and eliminated (Tmax , ∼1.1 hours; t1/2 , 4-11 hours) after administration of single (5-300 mg) and multiple (50 or 100 mg) doses. Receptor target engagement was confirmed for all doses, as indicated by an increase in serum
prolactin levels compared with placebo (mean
prolactin Cmax , 134.3 ng/mL after administration of
trazpiroben 10 mg vs 16.1 ng/mL with placebo). Therapeutically relevant single and multiple doses of
trazpiroben were well tolerated in healthy participants, and no clinically meaningful cardiovascular adverse effects were observed across the whole dose range. These data support the further development of
trazpiroben for the treatment of
gastroparesis.