Non-Clinical Safety Pharmacology Evaluations of Trazpiroben (TAK-906), a Novel Dopamine D2/D3 Selective Receptor Antagonist for the Management of Gastroparesis.

BACKGROUND: Gastroparesis 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. METHODS: Functional 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. RESULTS: No 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. DISCUSSION: Our results suggest that trazpiroben has limited central nervous system effects and a favorable cardiac safety profile.

Evaluating the Safety, Tolerability, and Disposition of Trazpiroben, a D2 /D3 Receptor Antagonist: Phase I Single- and Multiple-Ascending Dose Studies in Healthy Japanese Participants.

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).

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.

Pulmonary and nasal deposition of ketorolac tromethamine solution (SPRIX) following intranasal administration.

Ketorolac tromethamine is a racemic, non-steroidal, anti-inflammatory drug (NSAID). An intra-nasal (IN) formulation, SPRIX(®), is approved for the treatment of short term (up to 5 days) acute moderate to moderately severe pain. The primary objective of this study was to determine whether (99m)Tc-diethylenetriaminepenta acetic acid (DTPA) radiolabelled ketorolac tromethamine formulation (31.5 mg) was deposited in the lungs of healthy subjects (4 men and 9 women) following nasal inhalation of different intensities (gentle or vigorous sniff) and under different postural conditions (upright or semi-supine). The secondary objectives were to determine the deposition pattern of radiolabelled ketorolac solution in the nasal cavity and the clearance of the radiolabel over a 6h period post-administration. The nasal spray pump delivery device used showed a droplet size distribution with a volume mean diameter (VMD) of 50 µm and approximately 85% of the aerosol mass contained in droplets >10 µm diameter. The fraction of the dose recorded from the lung regions averaged <0.5%, and was considered to represent scattered radiation rather than true pulmonary deposition. This fraction was not affected by posture or by inhalation manoeuvre. The majority of the radiolabelled intranasal dose was deposited in the nasal cavity. The visual spread patterns within the nasal cavity were most uniform following administration in the upright position regardless of inhalation manoeuvre. Clearance from the nasal cavity was initially very rapid, with only 16-30% of the dose remaining after 10 min and 6-14% after 6 h. Retention was greatest following gentle inhalation.

Hair zinc concentrations not subject to seasonal variation in adults in New Zealand.

The analysis of recently grown hair for zinc provides a biomarker of recent zinc status. Seasonal variation of zinc in hair has been demonstrated in children. The aim of this study was to investigate whether on a month-by- month basis there is a seasonal variation in hair zinc concentration in an apparently well-nourished adult population in New Zealand. It was hypothesized that increased hours of daylight would be associated with an increase in zinc concentration in hair. Thirty-four subjects (20 F, 14 M) aged 18-54 yr had occipital hair sampled at monthly intervals between June and December. Food variety was assessed by questionnaire. After thorough washing of the hair followed by nitric acid digestion, zinc was determined by flame atomic absorption spectrometry (FAAS) with special attention to the inclusion of blanks, internal and international standards, and reduction of contamination in each sample run. Analyses between two laboratories confirmed that two FAAS instruments were giving the same reading. No seasonal variation in hair zinc concentration was found. Reported dietary variety, ethnicity, gender, and hair color were unrelated to hair zinc concentrations in this population. This study adds to evidence that will help define the role of hair zinc in determining recent zinc status.