TAK-906

Trazpiroben (TAK‐906) is a peripherally selective dopamine D2/D3 receptor antagonist being developed to treat chronic gastroparesis. This phase I, randomized, double‐blind, placebo‐controlled, single‐ and multiple‐ascending dose, parallel‐group 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).

Trazpiroben is a dopamine D2/D3 receptor antagonist under development for the treatment of gastroparesis. This phase I, open‐label, randomized, two‐way crossover study (NCT04121078) evaluated the effect of single‐dose intravenous rifampin, a potent inhibitor of the organic anion transporting polypeptides (OATPs) 1B1 and 1B3, on the pharmacokinetics and safety of trazpiroben in healthy adults. The utility of coproporphyrin (CP) I and CPIII as biomarkers of OATP inhibition was also assessed. Overall, 12 participants were enrolled and randomized (1:1) into one of two treatment sequences (AB and BA). Participants received either a single oral dose of trazpiroben 25 mg (treatment A) or a single oral dose of trazpiroben 25 mg immediately after a single 30‐min intravenous infusion of rifampin 600 mg (treatment B). After a washout period of at least 7 days, participants received the other treatment. Geometric mean area under the curve from time 0 extrapolated to infinity (AUC∞) and maximum serum concentration (Cmax) of plasma trazpiroben were higher in participants receiving treatment B than those receiving treatment A (AUC∞, 168.5 vs. 32.68 ng*h/ml; Cmax, 89.62 vs. 14.37 ng/ml); corresponding geometric mean ratios (90% confidence interval) showed 5.16 (4.25–6.25) and 6.24 (4.62–8.42)‐fold increases in these parameters, respectively. In this study, trazpiroben was confirmed as a substrate of OATP1B1/1B3, and therefore co‐administration of trazpiroben with moderate to strong inhibitors of OATP1B1/1B3 is not recommended. This is also the first assessment of the utility of CPI and CPIII as endogenous biomarkers of OATP1B1/1B3 inhibition after a single intravenous dose of rifampin.