Safety, Pharmacokinetics, and Pharmacodynamics of Trazpiroben (TAK‐906), a Novel Selective D2/D3 Receptor Antagonist: A Phase 1 Randomized, Placebo‐Controlled Single‐ and Multiple‐Dose Escalation Study in Healthy Participants

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.