Gastroparesis is a chronic gastric motility disorder characterized by delayed gastric emptying in the absence of any mechanical obstruction.1-3 Symptoms, which tend to be chronic with periods of exacerbation, typically include early satiety, postprandial fullness, nausea and vomiting, bloating, and upper abdominal pain.1 The majority of cases are idiopathic or secondary to surgery or diabetes,4 with diabetic gastroparesis considered a serious disease complication.5 Notably, gastroparesis significantly impacts patient quality of life, disrupting daily activities, and even reducing the annual income of those affected.6

Despite the associated disease burden, epidemiological data concerning gastroparesis are relatively limited, owing to the nonspecific nature of symptoms and difficulties in diagnosis. One study estimated the prevalence of clinically confirmed gastroparesis in the United States (2007 data) at 24.2 per 100 000 persons.7 There are no data for the prevalence of gastroparesis in Japan, possibly reflecting the absence of a standardized, accurate diagnostic procedure, and a poor awareness of the disease across Asia. In a recent survey of 490 physicians (including 133 physicians from Japan), half stated that they diagnosed <5 cases per year, with a quarter never diagnosing gastroparesis.8 However, considering that approximately one-third of patients with diabetes are thought to also have diabetic gastroparesis5 and that the prevalence of diabetes in Japan was estimated to be 7.9% in 2010 and was predicted to rise over the coming decade,9 there is the possibility that gastroparesis is frequently underdiagnosed in Japan.

Most current treatment strategies aim to increase gastric motility through a combination of dietary modifications, pharmacological intervention, and/or gastric electrical stimulation,1, 4 with antiemetics and prokinetics (such as D2/D3 receptor antagonists and 5-hydroxytryptamine 4 receptor agonists) frequently being employed.10-12 In particular, D2/D3 receptor antagonists have been shown to reduce the symptoms of gastroparesis by establishing normal gastric myoelectric activity and resolution of gastric dysrhythmias, which may be more pertinent to reducing symptoms than increasing gastric emptying alone.2, 10, 13, 14 Nonetheless, current treatment options for gastroparesis are limited; 2 agents with dopamine receptor antagonist activity, metoclopramide and domperidone, are available for the symptomatic management of gastroparesis in the United States, but carry safety concerns, namely, the risk of serious central nervous system (CNS) and cardiac adverse events (AEs), respectively.15-17

Trazpiroben (previously referred to as TAK-906 or ATC-1906M) is a novel, peripherally selective dopamine D2/D3 receptor antagonist under development for the treatment of gastroparesis. In vitro studies have shown that trazpiroben is primarily metabolized through a non–cytochrome P450 (CYP) pathway (56.7%) by multiple cytosolic, nicotinamide adenine dinucleotide phosphate–dependent reductases, with the remaining metabolism occurring through CYP3A4 (25.8%), CYP2C8 (11.8%), and other CYPs (5.7%).18 Metabolite M23 is a ketone product of trazpiroben, with aldo-keto reductases and short-chain dehydrogenases/reductases primarily involved in M23 formation.18 In a study of trazpiroben 25 mg administered to healthy participants, metabolite to parent ratios were 10.6%, with levels remaining consistent following co-administration of itraconazole.19 Investigation of drug-drug interactions showed that trazpiroben does not result in any significant direct inhibition of several of the major CYP isoforms (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A), and does not induce CYP isoforms when administered at a clinically relevant dose (0.06 μM).18 Additionally, an examination of inhibition of the CYP elimination route using itraconazole resulted in no substantial change in plasma trazpiroben levels,19 suggesting a low risk of drug-drug interaction via this mechanism. Trazpiroben has demonstrated selective antagonism of dopamine D2/D3 receptors in nonclinical in vivo studies, as well as being peripherally selective, and is thus unlikely to have CNS effects.20, 21 Trazpiroben was also shown to have low affinity for the human ether-à-go-go–related potassium channel, with no indication of affecting QRS duration, corrected QT interval (QTc) duration, or electrocardiogram (ECG) measurements,22 suggesting it is unlikely to affect cardiac repolarization or be associated with cardiovascular toxicities. In the first-in-human, single- and multiple-ascending dose phase I study conducted in 56 healthy participants in the United States (AT-01C study; NCT03268941),23 single and multiple doses of trazpiroben were well tolerated in healthy, predominantly White or Black men and women, and no clinically meaningful adverse effects, such as cardiovascular effects, were observed across the whole dose range (5-300 mg). Furthermore, a recent phase IIa study (NCT03268941) involving 51 patients with idiopathic or diabetic gastroparesis recruited from multiple US clinical research centers evaluated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profile of trazpiroben and did not identify any safety signals.24 Following prior analysis in US participants, further information is required on the safety, PK, and PD profile of trazpiroben in wider ethnic populations. The current study was conducted to evaluate the safety and tolerability, and the PK and PD of single and multiple oral doses of trazpiroben in healthy Japanese men. The study design was made consistent with that of the US AT-01C study,23 to allow informal comparison of intrinsic similarities and differences between the 2 populations.

Methods Study Design

This study was a phase I, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, parallel-group analysis conducted to assess the safety, tolerability, PK, and PD of trazpiroben administered as single and multiple doses in healthy male Japanese participants. A total of 24 participants were enrolled and split across 3 cohorts (each n = 8), who received trazpiroben in parallel. Participants in cohort 1 received trazpiroben 50 mg, while cohorts 2 and 3 received trazpiroben at a dose of 100 or 10 mg, respectively. In each cohort, 6 participants received active study drug and the other 2 received placebo (Table 1).

Table 1. Design of the Japanese Study Trazpiroben Dosea,b,c-a,b,c Single-dose period Multiple-dose periodd Patients (n) 10-mg single dose on day 1 10 mg twice daily for 5 days from days 3 through 7

6 trazpiroben

2 placebo

50-mg single dose on day 1 50 mg twice daily for 5 days from days 3 through 7

6 trazpiroben

2 placebo

100-mg single dose on day 1 100 mg twice daily for 5 days from days 3 through 7

6 trazpiroben

2 placebo

After a 27-day screening period, participants received a single dose of blinded study drug on day 1 (single-dose phase), followed by multiple doses of blinded study drug twice daily for 5 days from day 3 through day 7 (multiple-dose phase), without an evening dose of the study drug on day 7. Follow-up assessments occurred on day 14 (7 days after the completion of the last treatment dose). The study drug in the single-dose phase and all morning doses of the study drug in the multiple-dose phase were orally administered after a fast of at least 10 hours and that continued for at least 4 hours after dosing, with water intake prohibited for at least 1 hour before and after dosing. The evening dose was administered 12 hours after the morning dose and at least 2 hours after the evening meal. The design of the US AT-01C study has been described previously,23 and a schematic is provided in Figure S1 for comparison.

The proposed starting dose was 50 mg twice daily and the maximum dose permitted was 100 mg twice daily. Administration of trazpiroben 10 mg in cohort 3 was conducted in parallel with the other 2 cohorts. The safety and PK data gathered at the trazpiroben 10-mg and 50-mg doses were used to inform dose escalation in cohort 2, where participants were able to receive any dose up to 100 mg. Dose escalation from 50 to 100 mg was permitted only following a fully blinded review of safety and tolerability data for the 10- and 50-mg doses of trazpiroben. Any serious AE related to the study drug and any AE related to the study drug that made continued administration difficult were considered reasons not to escalate the dose.

The study was conducted in compliance with the institutional review board requirements stated in the Good Clinical Practice regulations and guidelines and was compliant with the principles expressed in the Declaration of Helsinki. The Houeikai institutional review board approved the clinical trial protocol, the investigator's brochure, a sample informed consent form, and other trial-related documents, and the study was performed at the Houeikai Medical Corporation, Sekino Clinical Pharmacology Clinic. All patients provided written consent for inclusion in the study.

Inclusion and Exclusion Criteria

The study included healthy Japanese men aged 20 to 60 years inclusive, with a body weight of 50 kg or higher and with a body mass index (BMI) of 18.5 to 25 kg/m2. Individuals with a history of seizure or tardive dyskinesia, hyperprolactinemia, pituitary adenoma, hypothyroidism, or any gastrointestinal disease that would be expected to influence the absorption of drugs were excluded, as were those with a family history of prolonged QT interval, a QTc using Fridericia's formula >450 milliseconds, previous gastric bypass surgery or current gastric band fitted, abnormal laboratory values of transaminase, bilirubin, or creatinine, or abnormal ECGs at screening or baseline before administration of the study drug. The inclusion and exclusion criteria used in the AT-01C study have previously been described.23

Safety and Tolerability

Safety measures evaluated in this study included AEs and physical and vital signs, in addition to ECG parameters. AEs were continuously monitored and assessed from the time the participant provided informed consent until follow-up at day 14. Assessment of vital signs and ECG monitoring (standard 12-lead ECG) were conducted before dosing and at 1, 2, 4, 6, and 24 hours after the single/morning dose on days 1, 2, 7, and 8. Vital signs were additionally assessed before the morning dose on days 3 through 6 and at follow-up on day 14, while ECG monitoring was additionally assessed before dosing and at 1 and 2 hours after the morning dose on day 5.

Pharmacokinetic Analysis

Blood samples for trazpiroben and its metabolite, M23 (pharmacologically inactive), were collected before dosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours after the single/morning dose on days 1, 2, 7, and 8, as well as before the morning dose on days 3 through 6. Urine samples for PK analyses were collected before dosing and at 0 to 6, 6 to 12, and 12 to 24 hours after dosing on days 1 and 2, as well as at 0 to 6 and 6 to 12 hours after the morning dose on day 7.

Plasma trazpiroben and M23 were quantified using a validated high-performance liquid chromatography with tandem mass spectrometric detection (LC-MS/MS) methods. These entities, along with their internal standards ([13C]-trazpiroben and [13C]-trazpiroben-M23), were isolated from human plasma using dipotassium ethylenediaminetetraacetic acid anticoagulant by protein precipitation. Extracted compounds were injected on reversed-phase column and separated by a gradient mobile phase composed of acetonitrile, methanol, water, ammonium formate, and formic acid. Eluting compounds were detected and quantified by TurboIonSpray in the positive ion mode and multiple reaction monitoring at transitions 518.2→232.1 (trazpiroben) and 520.2→232.1 (trazpiroben-M23). The calibration range was 0.05 to 50.00 ng/mL and the lower limit of quantification was 0.05 ng/mL for both analytes. Within-day accuracy and precision were relative error (RE) –2.7% to 8.2% and precision <7.5% (trazpiroben); and RE –4.0% to 8.4% and precision <6.5% (trazpiroben-M23). Between-day accuracy and precision were RE 1.3% to 5.0% and precision <6.7% (trazpiroben); RE –0.7% to 2.4% and precision <7.0% (trazpiroben-M23).

In urine, trazpiroben and its metabolite were quantified using a similar validated LC-MS/MS method. Analytes and their internal standards were isolated from human urine by addition of acetonitrile. Extracted compounds were injected onto a reversed-phase column and separated by a gradient mobile phase composed of acetonitrile, methanol, water, ammonium formate, and formic acid. Eluting compounds were detected and quantified by TurboIonSpray in the positive ion mode and multiple reaction monitoring at transitions 518.2→232.1 (trazpiroben), 520.2→232.1 (trazpiroben-M23). The calibration range was 5.0 to 5000.0 ng/mL and the lower limit of quantification was 5.0 ng/mL, for both analytes. Within-day accuracy and precision were RE –3.0% to 8.8% and precision <8.6% (trazpiroben); RE –6.4% to 6.7% and precision <5.7% (trazpiroben-M23). Between-day accuracy and precision were RE 0.0% to 3.4% and precision <6.2% (trazpiroben) and RE –3.0 to –0.5% and precision <4.7% (trazpiroben-M23). LC-MS/MS methods used for plasma and urine samples were validated by Covance Laboratories (Madison, Wisconsin).

Plasma PK parameters assessed included area under the concentration-time curve (AUC), maximum serum concentration (Cmax), time to Cmax (tmax), and elimination half-life (t1/2z), and urine measures such as total amount excreted, fraction of administered drug excreted in the urine and renal clearance. The PK parameters for trazpiroben and M23 were determined from the concentration-time profiles for all evaluable participants using high-performance liquid chromatography with LC-MS/MS. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times.

Pharmacodynamic Analysis

Serum prolactin concentrations were measured as a biomarker for dopamine D2 receptor antagonism. Samples were collected before dosing and at 1, 2, 4, 6, and 24 hours after the single/morning dose on days 1, 2, 7, and 8, immediately before the morning dose on days 3 through 6, and at follow-up on day 14. PD parameters assessed included AUC and Cmax, and were calculated from serum prolactin concentrations.

As for the PK analyses, blood samples intended for prolactin concentration determination were processed to serum, frozen, and stored at –70°C prior to analysis. Serum samples were analyzed using the in vitro ADVIA Centaur prolactin assay (Erlangen, Germany). The assay range is 0.3 to 200 ng/mL, and assay precision is <10%. Further details on the ADVIA Centaur assay have previously been published as part of the US AT-01-C study.23

Statistical Methods

The sample size of this study was considered sufficient for the evaluation of trazpiroben safety, tolerability, PK, and PD following oral single and multiple doses and was not based on statistical power considerations.

The PK and PD analysis sets consisted of participants who received at least 1 dose of the study drug, completed the minimum protocol-specified procedures with no significant deviations, and who were evaluable for PK or PD analyses, respectively. The safety set consisted of all participants who received at least 1 dose of the study drug.

Continuous variables for ECG parameters, clinical laboratory evaluations and vital signs, and AEs were summarized by dose across both dosing phases for each scheduled sampling time using descriptive statistics. For categorical variables, shift tables summarized the number of participants in each category at each postbaseline visit by category at baseline for each dose, with data summarized using descriptive summary statistics.

Plasma PK parameters for trazpiroben and M23 were summarized by dose for each scheduled sampling time using descriptive statistics; geometric means and coefficients of variation were computed for Cmax and AUC. Dose proportionalities for trazpiroben and M23 plasma exposures (Cmax and AUC) were assessed statistically across dose levels using linear and power function models, while urine PK parameters for trazpiroben and M23 were summarized by dose using descriptive statistics. For PD analysis of serum prolactin, the observed values and their changes from baseline were summarized by dose for each scheduled sampling time using descriptive statistics.

Results Participant Disposition and Baseline Demographics

In total, 24 participants were randomized; 18 received trazpiroben and 6 received placebo. Demographics were broadly comparable across dose groups (Table S1). Participants had a mean (standard deviation [SD]) age of 28.5 (5.8) years and a mean (SD) BMI of 21.8 (1.8) kg/m2. The Japanese participants in the present study were younger and had lower BMI than those in the US AT-01C study.23

Safety Analysis

There were no serious AEs or severe AEs in the study, and none of the participants discontinued treatment owing to AEs. Five treatment-emergent AEs (TEAEs) were reported, all of which were mild in intensity, and none of which were reported in >1 participant (Table 2). Three participants receiving trazpiroben experienced TEAEs, all of which were reported during the multiple-dose phase. There was 1 case of pharyngitis in a patient receiving trazpiroben 10 mg, and a single report in 1 participant each of increased creatinine and increased lactate dehydrogenase in the trazpiroben 100-mg group, none of which were considered related to the study drug. There were no QTc prolongation–associated TEAEs, neurologic TEAEs, or hyperprolactinemia–associated TEAEs reported during the study. Furthermore, there were no clinically significant findings from laboratory tests, vital signs, or ECG monitoring in participants receiving trazpiroben vs those receiving placebo. Safety findings were comparable to the US phase I study, which also found oral administration of single or multiple doses of trazpiroben to be well tolerated.

Table 2. Overview of TEAEs in Japanese Participants Number of Participants (%) Placebo (n = 6) Trazpiroben 10 mg (n = 6) Trazpiroben 50 mg (n = 6) Trazpiroben 100 mg (n = 6) Events Participants Events Participants Events Participants Events Participants Treatment-emergent AEs 2 1 (16.7) 1 1 (16.7) 0 0 (0.0) 2 2 (33.3) Related 2 1 (16.7) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) Not related 0 0 (0.0) 1 1 (16.7) 0 0 (0.0) 2 2 (33.3) Mild 2 1 (16.7) 1 1 (16.7) 0 0 (0.0) 2 2 (33.3) Moderate 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) Severe 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) Leading to study drug discontinuation 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) Infections and infestations 0 0 (0.0) 1 1 (16.7) 0 0 (0.0) 0 0 (0.0) Pharyngitis 0 0 (0.0) 1 1 (16.7) 0 0 (0.0) 0 0 (0.0) Investigations 1 1 (16.7) 0 0 (0.0) 0 0 (0.0) 2 2 (33.3) Alanine aminotransferase increased 1 1 (16.7) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) Blood creatinine increased 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 1 1 (16.7) Blood lactate dehydrogenase increased 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 1 1 (16.7) Renal and urinary disorders 1 1 (16.7) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) Proteinuria 1 1 (16.7) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) AE, adverse event; TEAE, treatment-emergent adverse event. Pharmacokinetic Analysis Plasma Concentrations

Following single and multiple doses of trazpiroben, the plasma concentration of trazpiroben peaked ≈1 hour after administration and rapidly decreased thereafter on both day 1 and day 7, with a slightly higher mean plasma concentration of trazpiroben on day 7 than on day 1 (Figure 1). Similarly, the plasma concentration of metabolite M23 reached a peak ≈1.0 to 1.5 hours after administration and then swiftly fell on days 1 and 7, with a slightly higher mean plasma concentration on day 7 vs day 1 (Figure S2). For both trazpiroben and M23, geometric mean concentration slopes during the elimination phase were similar between day 1 and day 7 and between doses. Trazpiroben demonstrated rapid absorption and elimination over 24 hours in both Japanese and US populations (Figure 2).

Mean (SD) plasma concentration–time curves of trazpiroben following single and multiple doses in Japanese participants. Plasma concentrations below the lower limit of quantification (0.05 ng/mL) were assigned a value of 0 ng/mL. SD, standard deviation.

Mean plasma concentration–time curves of trazpiroben following single and multiple doses in Japanese and US participants. Predose samples were assigned a sampling time of 0 hours. Plasma concentrations below the lower limit of quantification (0.05 ng/mL) were assigned a value of 0 ng/mL.

Plasma PK Parameters

During the single- and multiple-dose phases in Japanese participants, trazpiroben was shown to be rapidly absorbed (median tmax, 1 hour; and median tmax at steady state, 1.0-1.3 hours) and eliminated (mean t1/2z 1.9-5.2 hours [single-dose phase] and 3.7-6.5 hours [multiple-dose phase] across dosing groups; Table 3). The observed mean Cmax was 7.2 to 64.7 ng/mL during the single-dose phase and Cmax at steady state following multiple doses (Cmax,ss) was 8.0 to 81.8 ng/mL.

Table 3. Plasma PK Parameters of Trazpiroben in Japanese Participants Single-Dose Phase (Day 1) Trazpiroben 10 mg Trazpiroben 50 mg Trazpiroben 100 mg Variable Japanese (n = 6) US (n = 6) Japanese (n = 6) US (n = 6) Japanese (n = 6) US (n = 6) Cmax, ng/mL Mean (SD) 7.2 (2.0) 6.2 (1.9) 36.9 (12.3) 22.0 (6.9) 64.7 (28.5) 48.3 (23.1) %CV 28.4 30.2 33.2 31.3 44.0 47.8 tmax, h Median 1.0 0.9 1.0 1.1 1.0 1.8 AUC∞, ng • h/mL Mean (SD) 13.9 (2.2) 13.1 (4.4) 74.1 (17.3) 56.7a (11.6) 161.4 (38.1) 108.2b (24.7) %CV 15.6 33.8 23.4 20.4 23.6 22.9 AUClast, ng • h/mL Mean (SD) 13.6 (2.2) 12.9 (4.5) 73.4 (17.1) 53.2 (12.0) 159.6 (37.8) 103.8 (23.7) %CV 16.0 34.7 23.2 22.6 23.7 22.8 AUC24, ng • h/mL Mean (SD) 13.8 (2.2) 13.1 (4.4) 73.6 (17.0) 53.2 (12.1) 159.6 (37.8) 103.8 (23.7) %CV 15.9 33.8 23.0 22.7 23.7 22.8 t1/2z, h Mean (SD) 1.9 (0.9) 1.6 (0.2) 4.7 (3.8) 3.1 (0.4)a 5.2 (2.2) 5.4 (1.4)b %CV 45.0 14.6 81.8 13.0 41.7 26.5 CL/F, L/h