Preclinical Evaluation of the Effects of Trazpiroben (TAK-906), a Novel, Potent Dopamine D2/D3 Receptor Antagonist for the Management of Gastroparesis.

Current therapies for gastroparesis metoclopramide and domperidone carry risks of extrapyramidal symptoms and life-threatening cardiac arrhythmias. Trazpiroben, a novel, potent dopamine D2/D3 receptor antagonist, has low brain permeation and very low affinity for human ether-à-go-go-related gene (hERG) channel inhibition, potentially improving on safety profiles of existing therapies. Trazpiroben demonstrated the following receptor affinities: high for D2 and D3, moderate for D4, and minimal for D1 and D5 It demonstrated moderate affinity for adrenergic α 1B (α 1B) and 5-hydroxytryptamine (5HT) 2A receptors and low potential for off-target adverse events (AEs). Trazpiroben potently inhibited dopamine-activated D2L receptor activation of cognate G-proteins in human embryonic kidney 293 cell membranes and was a neutral D2L receptor antagonist. In vivo, trazpiroben dose-dependently increased prolactin release in orally dosed rat (0.1-1 mg/kg). Additionally, multiple oral doses in the rat (100 mg/kg) and dog (50 mg/kg) for 3 days produced robust plasma exposures and prolactin increases in both species. Trazpiroben inhibited retching/vomiting in the dog with apomorphine-induced emesis with a potency (0.1-1 mg/kg) like that of trazpiroben-mediated prolactin increases in rat. Oral trazpiroben (1, 10, and 30 mg/kg) did not affect rat rotarod performance, suggesting low brain penetration. Trazpiroben concentrations were low in cerebrospinal fluid versus plasma after multiple oral doses for 4 days in rat and dog. Trazpiroben weakly inhibited the hERG channel current (concentration causing half-maximal inhibition of control-specific binding of 15.6 µM), indicating little potential for disrupting cardiac rhythm. Overall, trazpiroben is a potent D2/D3 receptor antagonist designed to avoid the serious potential AEs associated with current gastroparesis therapies. SIGNIFICANCE STATEMENT: Trazpiroben is a novel, potent dopamine D2/D3 selective receptor antagonist designed to avoid adverse effects associated with the current pharmacological therapies metoclopramide and domperidone. Preclinical studies have demonstrated low brain penetration and weak affinity for the hERG channel, indicating that trazpiroben is not expected to be associated with central nervous system or cardiovascular safety issues. With these pharmacological properties, trazpiroben may represent a viable new treatment option for gastroparesis because of a potentially improved safety profile relative to existing therapies.

Safety, Pharmacokinetics, and Pharmacodynamics of Trazpiroben (TAK-906), a Novel Selective D2 /D3 Receptor Antagonist: A Phase 1 Randomized, Placebo-Controlled Single- and Multiple-Dose Escalation Study in Healthy Participants.

Gastroparesis is a chronic neuromuscular disorder of the upper gastrointestinal tract in which episodic exacerbation can lead to frequent hospitalizations and severe disability. Dopamine D2 /D3 receptor antagonists have been used to treat patients with gastroparesis with some efficacy; however, their chronic use is limited owing to associated central nervous system (CNS) or cardiovascular safety concerns. Trazpiroben (TAK-906) is a dopamine D2 /D3 receptor antagonist under development for the long-term treatment of gastroparesis. Preclinical studies in rat and dog have shown trazpiroben to have minimal brain penetration and low affinity for the human ether-à-go-go-related gene (hERG) potassium channel (IC50 ,  15.6 µM), thereby reducing the risk of the CNS and cardiovascular adverse effects seen with other dopamine D2 /D3 receptor antagonists. This phase 1 trial evaluated the safety, pharmacokinetics, and pharmacodynamics of trazpiroben in healthy participants. Trazpiroben was rapidly absorbed and eliminated (Tmax , ∼1.1 hours; t1/2 , 4-11 hours) after administration of single (5-300 mg) and multiple (50 or 100 mg) doses. Receptor target engagement was confirmed for all doses, as indicated by an increase in serum prolactin levels compared with placebo (mean prolactin Cmax , 134.3 ng/mL after administration of trazpiroben 10 mg vs 16.1 ng/mL with placebo). Therapeutically relevant single and multiple doses of trazpiroben were well tolerated in healthy participants, and no clinically meaningful cardiovascular adverse effects were observed across the whole dose range. These data support the further development of trazpiroben for the treatment of gastroparesis.