Randomised clinical trial: safety, pharmacokinetics and pharmacodynamics of trazpiroben (TAK‐906), a dopamine D 2 /D 3 receptor antagonist, in patients with gastroparesis
| العنوان: | Randomised clinical trial: safety, pharmacokinetics and pharmacodynamics of trazpiroben (TAK‐906), a dopamine D 2 /D 3 receptor antagonist, in patients with gastroparesis |
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| المؤلفون: | George Dukes, Chunlin Chen, Saurabh Gupta, Braden Kuo, Wenwen Zhang, Cecilia Scimia, Emil Chuang, Michael Camilleri |
| المصدر: | Alimentary Pharmacology & Therapeutics. 54:267-280 |
| بيانات النشر: | Wiley, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | medicine.medical_specialty, Hepatology, Gastric emptying, Metoclopramide, business.industry, Gastroenterology, Neurogastroenterology, Placebo, medicine.disease, Domperidone, 03 medical and health sciences, 0302 clinical medicine, Tolerability, Dopamine receptor D3, Internal medicine, medicine, 030211 gastroenterology & hepatology, Pharmacology (medical), 030212 general & internal medicine, Gastroparesis, business, medicine.drug |
| الوصف: | Background Gastroparesis is a chronic gastric motility disorder. Dopamine D2 /D3 receptor antagonists metoclopramide and domperidone are current treatment options but are associated with central nervous system and cardiovascular safety concerns, respectively, precluding chronic use. Trazpiroben (TAK-906), a dopamine D2 /D3 receptor antagonist, is under development for chronic treatment of moderate-to-severe gastroparesis. Nonclinical data suggest trazpiroben will have D2 /D3 receptor antagonism comparable with metoclopramide or domperidone. Aims To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics (effect on prolactin and gastric function) of twice-daily trazpiroben (5, 25 and 100 mg) in participants with gastroparesis. Methods This phase 2a pilot study evaluated gastric emptying using the gastric emptying breath test, with metoclopramide as an internal control. Gastric accommodation and gastroparesis symptoms were assessed using the nutrient drink test and American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary, respectively. Results Overall, 51 participants were enrolled. Trazpiroben was well tolerated, demonstrating a favourable safety profile without cardiovascular or central nervous system adverse events. All trazpiroben doses were rapidly absorbed and eliminated (t1/2z 4-5 hours), and D2 /D3 receptor target engagement confirmed by increased serum prolactin (peaking at trazpiroben 25 mg). No effect on gastric emptying was demonstrated with trazpiroben or metoclopramide (P > 0.05), although benefits in volume-to-fullness were seen at trazpiroben 5 mg (P > 0.05) and 25 mg (88.5 vs -26.3 mL; P = 0.019), and nonsignificant numerical aggregate symptom score improvements were observed with trazpiroben 25 mg vs placebo (P = 0.182). Conclusions Trazpiroben was well tolerated with a favourable safety profile, supporting its further development for the treatment of gastroparesis. ClinicalTrials.gov identifier: NCT03268941. |
| تدمد: | 1365-2036 0269-2813 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::577c25231179dde89d971a00607fa378 https://doi.org/10.1111/apt.16451 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........577c25231179dde89d971a00607fa378 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13652036 02692813 |
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