Evaluating the Safety, Tolerability, and Disposition of Trazpiroben, a D₂/D₃ Receptor Antagonist: Phase I Single‐ and Multiple‐Ascending Dose Studies in Healthy Japanese Participants

Abstract

Trazpiroben (TAK-906) is a peripherally selective dopamine D 2 /D 3 receptor antagonist being developed to treat chronic gastroparesis. This phase I, randomized, double-blind, placebo-controlled, single-and multiple-ascending dose, parallelgroup study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of trazpiroben in healthy Japanese men.Findings were compared with those from a prior US trial in healthy individuals.Overall,24 participants were enrolled into 3 cohorts (each n = 8). Per cohort, 6 participants received trazpiroben (cohort 1, 50 mg; 2, 100 mg; 3, 10 mg) once on day 1 and twice daily on days 3 through 7, and two received placebo. Trazpiroben was well tolerated, with no clinically meaningful adverse events observed.Following single-and multiple-dose administration,trazpiroben was rapidly absorbed and eliminated (mean elimination half-life, 1.89-6.45 hours; median time to maximum serum concentration [steady state], 1.00-1.25 hours). Serum prolactin increased with trazpiroben treatment (mean maximum serum concentration 93.32 ng/mL [10 mg] vs. 10.83 ng/mL [placebo]), illustrating receptor target engagement. Results reflected those from healthy US participants, indicating a lack of differences between these ethnic populations in trazpiroben disposition and safety profile.Trazpiroben may represent a promising therapy for chronic gastroparesis across different populations,with further evaluation ongoing in a phase IIb study (NCT03544229).

Randomized clinical trial: A phase 2b controlled study of the efficacy and safety of trazpiroben (TAK‐906) for idiopathic or diabetic gastroparesis

“…Previous in vitro and animal studies demonstrated that trazpiroben selectively antagonizes D 2 /D 3 receptors with limited central nervous system penetrance, and also shows low affinity for the hERG potassium channel 16,17 . With respect to human studies, trazpiroben was well tolerated in phase 1 clinical trials (NCT03237156) and during phase 1 clinical pharmacology studies 18–22 . A phase 2a study (NCT03268941) assessed the safety profile, pharmacokinetics (PK), and pharmacodynamics of trazpiroben in patients with gastroparesis, with pharmacodynamics evaluated by the effect of trazpiroben on prolactin levels and gastric function 23 .…”

“…16,17 With respect to human studies, trazpiroben was well tolerated in phase 1 clinical trials (NCT03237156) and during phase 1 clinical pharmacology studies. [18][19][20][21][22] A phase 2a study (NCT03268941) assessed the safety profile, pharmacokinetics (PK), and pharmacodynamics of trazpiroben in patients with gastroparesis, with pharmacodynamics evaluated by the effect of trazpiroben on prolactin levels and gastric function. 23 This phase 2a study showed significantly improved volume-to-fullness following the nutrient drink test, and improved American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary (ANMS GCSI-DD) symptom scores with trazpiroben, further supporting its development to treat gastroparesis.…”