Evaluation of the pharmacokinetics of trazpiroben (TAK‐906) in the presence and absence of the proton pump inhibitor esomeprazole

Trazpiroben, a dopamine D₂/D₃ receptor antagonist under development to treat gastroparesis, displays decreasing solubility with increasing pH. This single‐sequence, open‐label, two‐period, crossover study evaluated the effect of esomeprazole, a proton pump inhibitor that raises gastric pH, on the single‐dose pharmacokinetics, safety, and tolerability of trazpiroben in healthy adults ({"type":"clinical-trial","attrs":{"text":"NCT03849690","term_id":"NCT03849690"}}NCT03849690). In total, 12 participants were enrolled and entered period 1 (days 1–3), receiving a single oral dose of trazpiroben 25 mg on day 1. After a 4‐day washout, participants then entered period 2 (days 8–13) and received esomeprazole 40 mg once daily on days 8–12, with a single oral dose of trazpiroben 25 mg co‐administered 1 h post esomeprazole dosing on day 11. Geometric mean area under the curve from time 0 extrapolated to infinity (AUC_∞) and maximum plasma concentration (C_max) values were generally similar when trazpiroben was administered alone versus alongside esomeprazole (AUC_∞, 44.03 vs. 38.85 ng h/ml; C_max, 19.76 vs. 17.24 ng/ml). Additionally, the associated geometric mean ratio (GMR; co‐administration: administration alone) 90% confidence intervals (CIs) suggested no clinically meaningful difference between treatment groups (AUC_∞, GMR 0.88, 90% CI 0.78–1.00; C_max, 0.87, 90% CI 0.70–1.09). Mean apparent first‐order terminal elimination half‐life values were similar between treatments, illustrating co‐administration with esomeprazole had minimal effect on trazpiroben elimination. Trazpiroben was well‐tolerated in healthy adults following administration alone and alongside esomeprazole, with no clinically relevant adverse events reported. The lack of evidence of any clinically meaningful drug–drug interaction supports the co‐administration of esomeprazole with trazpiroben.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Gastroparesis is a gastric motility disorder typified by delayed gastric emptying without mechanical obstruction, with affected patients experiencing a range of gastrointestinal symptoms. Patients with gastroparesis may experience symptom overlap with, or comorbid, gastroesophageal reflux disease. Proton pump inhibitors (PPIs), which raise gastric pH, are frequently used to provide symptomatic relief. Trazpiroben is a dopamine D₂/D₃ receptor antagonist under development to treat gastroparesis. Given that trazpiroben displays decreasing solubility with increasing pH, the potential for a drug–drug interaction (DDI) with a PPI was evaluated.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the effect of the PPI esomeprazole on the single‐dose pharmacokinetics, safety, and tolerability of trazpiroben in healthy adults.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The results of this study demonstrated no evidence of any clinically meaningful DDI between trazpiroben and esomeprazole. Trazpiroben was well‐tolerated following administration alone and alongside esomeprazole, with no clinically relevant adverse events reported.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The current treatment landscape for gastroparesis is limited, with use of available therapies restricted by safety concerns. Our findings support the potential co‐administration of trazpiroben and esomeprazole, indicating that trazpiroben could represent a promising treatment option for patients with gastroparesis who are receiving PPI therapy.