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

ABSTRACT: 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 (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.

SUBMITTER: Kaur Mukker J

PROVIDER: S-EPMC9099131 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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

Kaur Mukker Jatinder J Dukes George G Wang Lisi L Huh Susanna S Khudyakov Polyna P Nishihara Mitsuhiro M Chen Chunlin C

Clinical and translational science 20220226 5

Trazpiroben, a dopamine D<sub>2</sub> /D<sub>3</sub> 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 (NCT03849690). In total, 12 participants were enrolled and entered period 1 (days 1-3), rec ...[more]

PMID: 35218604

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Project description:BackgroundGastroparesis is characterized by delayed gastric emptying in the absence of mechanical obstruction. Owing to the potential for serious side effects, current treatments have restrictions on their use and there is a need for novel compounds with favorable safety profiles. Trazpiroben (previously TAK-906) is a peripherally selective dopamine D2/D3 receptor antagonist being developed to treat chronic gastroparesis. Effects of trazpiroben on the central nervous system and pulmonary system in rats and on the cardiovascular system in dogs were assessed.MethodsFunctional observational battery and locomotion assessments were conducted in groups of eight female rats receiving 0 (control), 100, 300, or 1000 mg/kg/day oral trazpiroben for 2 days. Assessments were performed at baseline (pre-dosing) and 0.5 hours post-dose on day 2 of dosing. Pulmonary safety: following administration of the same trazpiroben doses, groups of eight male rats underwent heads-out plethysmography at baseline, through 6 hours post-dose, and approximately 24 hours post-dose on day 1. Four telemetry-instrumented male beagle dogs received 0 (control), 1, 10, or 30 mg/kg of oral trazpiroben in a Latin square crossover design on days 1, 4, 8, and 11. Relevant parameters were continuously measured for approximately 18 hours post-dose.ResultsNo clinically meaningful effects on central nervous system, pulmonary, or cardiovascular assessments were observed at any trazpiroben dose. Significantly decreased locomotion occurred with increasing dose, including reduced horizontal/vertical ambulation at ≥ 300 mg/kg/day. Small transient decreases in systolic and pulse pressure at ≥10 mg/kg/day were observed, with compensatory increases in heart rate at 30 mg/kg/day. No trazpiroben-related effects on cardiovascular parameters (including QT interval corrected for heart rate) or body temperature were noted. No trazpiroben-related qualitative electrocardiogram abnormalities were observed.DiscussionOur results suggest that trazpiroben has limited central nervous system effects and a favorable cardiac safety profile.

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Dataset Information

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

Publications

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

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