Abstract
Background and Objectives
Dotinurad is a selective uricosuric drug for patients with gout with hyperuricemia. To our knowledge, this is the first study to evaluate the pharmacokinetics (PK) of dotinurad, following single and multiple oral doses in healthy Chinese adults.
Methods
This single-center, open-label, parallel group, phase 1 study had 3 cohorts: A (1-mg single dose), B (single and multiple doses of 4 mg once daily for 7 days), and C (10-mg single dose). Dotinurad was administered on an empty stomach. Healthy nonsmoking Chinese adults aged 18–45 years with body mass index 19–24 k/m2 and weight ≥ 50 kg were enrolled; Cohort B required serum urate ≥ 5.5 mg/dL at screening.
Results
In total, 26 subjects were included. After single oral doses of 1, 4, and 10 mg, mean ± standard deviation (SD) plasma dotinurad concentration reached maximum observed plasma concentration (Cmax) of 104 ± 18.5, 365 ± 35.2, and 964 ± 101 ng/mL at 3.00–3.50 h, respectively. The mean ± SD terminal elimination phase half-life was 10.1 ± 1.26, 9.87 ± 1.47, and 10.9 ± 1.53 h for the 1, 4, and 10 mg doses, respectively; both area under the plasma concentration-time curve and Cmax increased in a dose-proportional manner across the 1–10-mg dose range. During once-daily doses for 7 days, steady state was reached by the 2nd day after the initiation of multiple dosing, with an average steady-state plasma concentration of 186 ± 31.8 ng/mL, indicating minimal accumulation. Treatment-emergent adverse events (TEAEs) occurred in four subjects (15.4%); all were mild and resolved without treatment. No dose-dependent TEAEs were observed.
Conclusion
Single- and multiple-dose PK of dotinurad in healthy Chinese adults showed rapid absorption, rapid elimination, linear PK, and no accumulation with once-daily dosing. Dotinurad was well-tolerated during the 7-day treatment course.
Trial Registration
ClinicalTrials.gov: NCT05278676.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40261-025-01496-x.
Key Points
| The pharmacokinetic profiles of dotinurad following single and multiple doses in healthy Chinese subjects were found to be comparable to those previously reported in healthy Japanese subjects. |
| No specific safety concerns were identified. |
Introduction
Gout is caused by hyperuricemia, which is defined as a serum urate level exceeding approximately 7.0 mg/dL [1, 2]. Persistent hyperuricemia can lead to urate crystal deposition, which in turn causes inflammatory arthritis [1, 3]. In 2019, the number of patients with gout in China was estimated to be 16.2 million [4], and in 2020, the prevalence of gout in China was estimated to be 1.3% [5]. In recent years, the prevalence has been steadily increasing in China [6] and globally, possibly because of changes in dietary patterns, with a shift toward high-fat diets, along with increased life expectancy among the population [7, 8]. Gout was reported to be an independent risk factor for chronic kidney disease, hypertension, coronary heart disease, cardiovascular disease, and type 2 diabetes, as well as an independent predictor of premature death and cardiovascular mortality [3, 9, 10].
Effective management of hyperuricemia is important for preventing complications, such as gout flare, urate nephropathy, and urinary calculi [11, 12]. Effective management may also protect renal function and reduce the risk of cardiovascular disorders [13, 14]. Hyperuricemia can be classified based on its etiology, which involves excessive production of uric acid, decreased excretion of uric acid, or a combination of both (combined-type hyperuricemia). In China, approximately 90% of hyperuricemia cases are caused by decreased excretion of uric acid or are the combined type [15].
Some treatment options for hyperuricemia include allopurinol, febuxostat, and topiroxostat, which are xanthine oxidase inhibitors that reduce uric acid production. However, not all patients reach those treatments’ target serum urate levels [16]. In addition, allopurinol is associated with various adverse drug reactions such as gastrointestinal events, rash, and sometimes fatal dermatological reactions (e.g., Stevens–Johnson’s syndrome) [17]. Although febuxostat has been increasingly prescribed in recent years, it has been associated with a higher risk of hepatotoxicity, cardiovascular death, and all-cause mortality [18, 19]. Benzbromarone is a uricosuric drug that reduces the reabsorption of uric acid in the proximal tubule; although withdrawn from the European market due to serious hepatotoxicity [20], it is still commonly prescribed in several countries in Asia, including China. Therefore, a well-tolerated and selective uricosuric drug that does not cause hepatic impairment is needed for use in clinical practice.
Dotinurad is a selective urate reabsorption inhibitor that has been shown to significantly improve serum urate levels in patients with hyperuricemia [21–23]. Reduced serum urate levels are achieved through selective inhibition of the urate transporter 1, which is expressed on the proximal renal tubules and is responsible for reabsorption of uric acid [24]. Dotinurad is primarily metabolized by UDP-glucuronosyltransferase (UGT) and sulfotransferase into glucuronide and sulfate conjugates, and is mainly excreted via the kidneys [25]. Approval of dotinurad was granted in January 2020 for the treatment of hyperuricemia and gout in Japan ahead of the rest of the world [26], and most of the clinical pharmacology studies of dotinurad have been conducted in Japanese populations [22, 23, 27–31]. In a recent study in Chinese patients with gout, dotinurad reduced serum urate by 37.9% at 2 mg (Week 12) and 45.9% at 4 mg (Week 24) [32]. In addition, recent clinical trials in Japanese patients with hyperuricemia treated with dotinurad demonstrated its serum urate-lowering effect, along with additional benefits such as preserving kidney function [33–35] and providing vascular protection [36].
In China, dotinurad was approved in December 2024 for the treatment of patients with gout with hyperuricemia; the clinical maintenance dosage is 2–4 mg once daily according to the patient’s condition [37]. Dotinurad was absorbed quickly following oral administration in a fasted state in Japanese subjects, with systemic exposure increasing in a dose-proportional manner, can be administered with or without food, and does not exhibit any accumulation after once-daily dosing [30, 38]. However, the pharmacokinetic (PK) characteristics of dotinurad in healthy Chinese subjects and differences among Asian populations had not been investigated.
The primary objective of this study was to evaluate the PK of dotinurad following single and multiple oral doses in healthy Chinese subjects. The secondary objectives were to evaluate the safety and tolerability of dotinurad following single and multiple oral doses and to evaluate the dose proportionality of the PK of dotinurad following a single oral dose in healthy Chinese subjects.
Methods
Study Design and Intervention
This was a single-center, single- and multiple-oral-dose, open-label, parallel group, phase 1 study conducted in healthy Chinese adult subjects. This study was conducted from July to December 2022.
An overview of the study design is shown in Online Resource 1. Subjects were enrolled into three cohorts (Cohorts A, B, and C) and administered dotinurad. The study had two phases (Pretreatment Phase and Treatment Phase). The Pretreatment Phase comprised a Screening Period (Days − 28 to − 2) and a Baseline Period (Day − 1); the Treatment Phase consisted of a 3-day Treatment Period (Days 1–3) in Cohorts A and C and a 13-day Treatment Period (Days 1–13) in Cohort B. Subjects were admitted to the site on Day − 1 (the day before the study drug administration) and discharged from the clinic site on Day 3 in Cohorts A and C, and on Day 13 in Cohort B upon completion of study procedures.
Dotinurad was orally administered as 1- or 2-mg tablets. Cohort A received a single dose of 1 mg of dotinurad (1 × 1 mg dotinurad tablet), Cohort B received a single dose and multiple doses of 4 mg of dotinurad (2 × 2 mg dotinurad tablets), and Cohort C received a single dose of 10 mg of dotinurad (5 × 2 mg dotinurad tablets). In Cohorts A and C, a single dose of the study drug was administered on Day 1 in the morning after 10-h fasting. In Cohort B, subjects received a single dose of the study drug on Day 1 in the morning after 10-h fasting, and after a 3-day washout period, subjects received multiple doses of the study drug for 7 days from Day 4 to Day 10 once daily in the morning after 10-h fasting. The use of prescription drugs within 4 weeks before the first dosing and throughout the study and the intake of over-the-counter medications within 2 weeks before first dosing and throughout the study were prohibited.
The doses for the single-dose part (1, 4, and 10 mg) were selected on the basis of the planned clinical starting dose and maintenance dose in Chinese patients with gout and to allow comparison with previously reported Japanese phase 1 studies. The 1-mg dose represents the starting dose, 4 mg corresponds to the clinical maintenance dose, and 10 mg was chosen as the high dose for safety and PK comparison purposes. The multiple-dose regimen (4 mg once daily for 7 days) was selected to evaluate steady-state PK at the clinical maintenance dose and to allow comparison with a Japanese multiple-dose study. Sample sizes and cohort composition were determined in accordance with the Chinese Technical Guidelines for Clinical Single- and Multiple-Dose PK Studies, with at least 3 female participants included in each cohort
The protocol was approved by the ethics committee of Shanghai Xuhui Central Hospital (approval number 2022-002). The study was conducted in accordance with the Declaration of Helsinki and Chinese Good Clinical Practice guidelines and all applicable regulations. All subjects provided written informed consent. The study was registered at ClinicalTrials.gov under the identifier number NCT05278676.
Participants
Subjects were included if they met all of the following criteria: healthy, nonsmoking, Chinese male or female, aged 18–45 years at the time of informed consent, with body mass index (BMI) of 19–24 kg/m2, and weighing ≥ 50 kg at screening. In Cohort B, subjects with a serum urate level ≥ 5.5 mg/dL at screening were eligible to participate to avoid excessive reduction in serum urate levels following multiple doses.
The main exclusion criteria were as follows: clinically significant illness or infection that required medical treatment within 8 or 4 weeks of dosing, respectively; evidence of disease that might influence the outcome of the study within 4 weeks before dosing; history of urinary calculi or diagnosed urinary calculi at screening; history of gastrointestinal surgery that might affect PK profiles of dotinurad at screening; prolongation of the QT interval at screening or baseline; and breastfeeding or pregnant female subjects at screening or baseline or those desiring to get pregnant during the study period.
Sample Collection and Bioanalytical Assay
In all cohorts, venous blood samples of approximately 4 mL were collected in anticoagulant-containing tubes for PK assessments at predose (Day 1); at 0.5, 1, 2, 3, 4, 6, 8, and 12 h postdose (Day 1); and 24 h (Day 2) and 48 h (Day 3) postdose. In Cohort B only, blood samples were collected at predose (Days 4, 6, 8, and 10); at 0.5, 1, 2, 3, 4, 6, 8, and 12 h postdose (Day 10); and at 24, 48, and 72 h postdose on Day 10 (Days 11, 12, and 13, respectively).
Whole blood samples were centrifuged at 2000 g for 10 min at 4 °C within 30 min of collection to separate plasma. The resulting plasma was divided into two aliquots in cryovials, and all aliquots were immediately stored in an ultra-low temperature freezer (− 80 °C ± 10 °C) until analysis. For bioanalysis, plasma samples were passed through a solid-phase column for pretreatment, and plasma concentrations of dotinurad in diluted samples were quantified by liquid chromatography with tandem mass spectrometry methodology at Frontage Laboratories (Shanghai) Co., Ltd. (Shanghai, China). Triple Quad 6500+ (Sciex, USA) was used for Tandem mass spectrometry, with a Shim-Pack GIST-HP (50 × 2.1 mm, 3 μm: Shimadzu, Japan) for column analysis, and 5 mmol/L ammonium acetate solution/methanol for the mobile phase. The limit of quantification was 1 ng/mL for the dotinurad concentration measurement in plasma. The mass spectrometer was operated in negative electrospray ionization mode, with unit resolution for both Q1 and Q3. The multiple reaction monitoring transition was m/z 356.0 → 159.9 for dotinurad and m/z 341.1 → 145.0 for the internal standard. The interrun accuracy ranged from − 9.7 to − 2.8% with interrun precision < 4.9%. The intrarun accuracy ranged from − 13.7 to 0.0% with intrarun precision of 4.8%. All results were within the predefined acceptance criteria of ±15%. At the lower limit of quantitation of 1.00 ug/mL, the interrun accuracy was − 1.8%; interrun precision was 15.0%; intrarun accuracy ranged from − 18.1 to 10.0%; intrarun precision was < 13.0%; and all results were within the predefined acceptance criteria of ±20%. The calibration curve ranged from 1.00 ng/mL to 500 ng/mL for dotinurad (Online Resource 2).
Outcomes
Age at the time of informed consent, sex, weight, and BMI data were collected at screening/baseline. The following PK parameters were evaluated in all three cohorts: area under the plasma concentration–time curve (AUC) from time zero to infinity (AUC0–inf), AUC from time zero to the last measurable sample point (AUC0–t), AUC from time zero to 24 h (AUC0–24h), maximum observed plasma concentration (Cmax), time to reach peak plasma concentration (tmax), terminal elimination phase half-life (t½), apparent total clearance following oral administration (CL/F), and apparent volume of distribution at terminal phase (Vz/F).
The following PK parameters were evaluated in Cohort B only: AUC over the dosing interval on multiple dosing (AUC0–τ), maximum observed concentration at steady state (Css,max), minimum observed concentration at steady state (Css,min), average steady-state concentration (Css,av), time at which the highest drug concentration occurs at steady state (tss,max), apparent total clearance following oral administration at steady state (CLss/F), accumulation ratio for AUC0–24h (Rac(AUC0–24h)), and accumulation ratio for maximum observed concentration (Rac(Cmax)).
Safety assessments comprised treatment-emergent adverse events (TEAEs); laboratory evaluation for hematology, blood chemistry, and urinalysis; vital signs; weight; 12-lead electrocardiogram (ECG) results; and physical examinations. Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities (MedDRA®), version 25.0.
Statistical Methods
A sample size of eight subjects each in Cohorts A and C was determined based on the Chinese guidelines for PK research [39], although no formal statistical criteria were applied in the sample size determination. In Cohort B, to account for potential dropouts during multiple dosing, the sample size was set at 10 subjects. According to the Technical Guidelines for Single and Multiple Ascending Dose Pharmacokinetic Studies of Innovative Chemical Drugs, each cohort should include both male and female subjects [40], with a minimum of three female subjects to allow for sex-based summary statistics as needed.
The safety analysis set included all subjects who received at least 1 dose of the study drug and had at least 1 postdose safety assessment. The PK analysis set included all subjects who received at least 1 dose of the study drug and had sufficient PK data to derive at least one PK parameter.
Frequencies were calculated for categorical data and mean ± standard deviation or median (min–max) for continuous data. The PK parameters for dotinurad were estimated by noncompartmental methods. Dose proportionality for Cmax, AUC0–t, and AUC0–inf (over the 1–10-mg dose range after a single dose) was evaluated using a linear model of logarithmically transformed values to assess the slope parameter as well as its 95% confidence intervals (CIs). All statistical analyses were performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA). Noncompartmental PK parameter calculations were performed using Phoenix WinNonlinTM 8.3.5 (Certara, L.P., Princeton, New Jersey, USA).
Results
Study Participants
In total, 134 subjects were screened, among whom 108 were screening failures. In total, 26 subjects were included in the study and received study treatment: 8 in Cohort A, 10 in Cohort B, and 8 in Cohort C. All 26 subjects completed the planned treatment and were included in the safety analysis set and PK analysis set. There were no missing or excluded data.
The baseline demographic and clinical characteristics of the safety analysis set are summarized in Table 1. All 26 subjects were Asian (Chinese) and the median (min–max) age was 31 (18–43) years. Five (62.5%) male and 3 (37.5%) female subjects were enrolled in both Cohorts A and C; 7 (70%) male and 3 (30%) female subjects were enrolled in Cohort B. The median BMIs in Cohorts A, B, and C were 22.5, 22.5, and 22.2 kg/m2, respectively. There were no notable differences between the three cohorts regarding baseline characteristics.
Table 1.
Baseline demographic and clinical characteristics (safety analysis set)
| Cohort A Dotinurad 1 mg, N = 8 |
Cohort B Dotinurad 4 mg, N = 10 |
Cohort C Dotinurad 10 mg, N = 8 |
Total, N = 26 | |
|---|---|---|---|---|
| Age, years | 29 (18–37) | 32 (25–38) | 28 (21–43) | 31 (18–43) |
| Sex | ||||
| Male | 5 (62.5) | 7 (70.0) | 5 (62.5) | 17 (65.4) |
| Female | 3 (37.5) | 3 (30.0) | 3 (37.5) | 9 (34.6) |
| Chinese race | 8 (100.0) | 10 (100.0) | 8 (100.0) | 26 (100.0) |
| Weight, kg | 65.8 (54.2–69.2) | 60.7 (51.1–72.6) | 60.2 (52.3–74.6) | 62.1 (51.1–74.6) |
| BMI, kg/m2 | 22.5 (20.9–24.5) | 22.5 (20.1–24.3) | 22.2 (20.3–23.3) | 22.3 (20.1–24.5) |
Data are median (min–max) or n (%)
BMI body mass index
Pharmacokinetics
The mean plasma concentration–time curves of dotinurad after single oral doses are shown in Fig. 1. After single oral doses of dotinurad from 1 to 10 mg, the mean plasma concentration of dotinurad reached maximum concentration at 3.00–3.50 h after dosing across all dose groups and decreased to below 10% of the corresponding maximum concentration within 48 h.
Fig. 1.
Mean plasma concentrations of dotinurad after a single dose in all cohorts (0–48 h postdose on Day 1); PK analysis set: a linear scale and b semi-logarithmic scale. Error bars indicate standard deviation. PK pharmacokinetic
The PK parameters of single-dose dotinurad are summarized in Table 2. After single oral doses of dotinurad from 1 to 10 mg, the AUC0–24h, AUC0–t, AUC0–inf, and Cmax increased with increasing dose. The CL/F and Vz/F were constant across the dose range of 1–10 mg at 0.757–0.834 L/h and 11.1–11.7 L, respectively. The mean t½ was approximately 10 h and was consistent across all dose groups.
Table 2.
Pharmacokinetic parameters after a single dose of dotinurad (pharmacokinetic analysis set)
| Pharmacokinetic parameter | Cohort A Dotinurad 1 mg, N = 8 |
Cohort B Dotinurad 4 mg, N = 10 |
Cohort C Dotinurad 10 mg, N = 8 |
|---|---|---|---|
| AUC0–inf, ng·h/mL | 1360 ± 288 | 4890 ± 683 | 13600 ± 2480 |
| AUC0–t, ng·h/mL | 1300 ± 268 | 4700 ± 608 | 12900 ± 2130 |
| AUC0–24h, ng·h/mL | 1080 ± 213 | 3950 ± 415 | 10600 ± 1460 |
| Cmax, ng/mL | 104 ± 18.5 | 365 ± 35.2 | 964 ± 101 |
| tmax, h | 3.50 (2.00–6.00) | 3.00 (2.00–4.00) | 3.00 (1.02–6.02) |
| t½, h | 10.1 ± 1.26 | 9.87 ± 1.47 | 10.9 ± 1.53 |
| CL/F, L/h | 0.764 ± 0.147 | 0.834 ± 0.130 | 0.757 ± 0.134 |
| Vz/F, L | 11.1 ± 2.06 | 11.7 ± 1.12 | 11.6 ± 1.10 |
Data are shown as mean ± standard deviation except tmax, where median (min–max) is shown
AUC0–24h area under the concentration–time curve from 0 to 24 h, AUC0–inf area under the concentration–time curve from 0 extrapolated to infinite time, AUC0–t area under the concentration–time curve from 0 to time of last quantifiable concentration, CL/F apparent total clearance following oral administration, Cmax maximum observed concentration, t½ terminal elimination phase half-life, tmax time at which the highest drug concentration occurs, Vz/F apparent volume of distribution at terminal phase
The dose proportionality of dotinurad derived from PK parameters following single oral doses is shown in Table 3. The 95% CIs for the assessment of dose proportionality using the power model included 1, indicating linear PKs for dotinurad across the dose range of 1–10 mg.
Table 3.
Dose proportionality after a single dose of 1–10 mg of dotinurad based on the power model (pharmacokinetic analysis set)
| Pharmacokinetic parameter | β1 (95% CI) |
|---|---|
| AUC0–t, ng·h/mL | 0.993 (0.919–1.07) |
| AUC0–inf, ng·h/mL | 0.996 (0.917–1.08) |
| Cmax, ng/mL | 0.966 (0.908–1.03) |
Dose proportionality for AUC0–t, AUC0–inf, and Cmax was assessed by linear regression of ln-transformed parameters on the natural ln-transformed dose [ln(PK parameter) = β0 + β1 × ln(dose)] (Power Model).
AUC0–inf area under the concentration–time curve from 0 extrapolated to infinite time, AUC0–t area under the concentration–time curve from 0 to time of last quantifiable concentration, β1 values of the proportionality constant, CI confidence interval, Cmax maximum observed concentration, ln natural log
The mean plasma concentration–time curves of dotinurad after multiple oral doses are shown in Figure 2. After multiple oral doses of dotinurad of 4 mg once daily for 7 days from Day 4 to Day 10, the mean plasma concentrations of dotinurad on Day 10 reached the maximum concentrations at 3.00 h after dosing and decreased to below 1% of the corresponding maximum concentrations within 72 h. The mean trough concentrations on Day 6, Day 8, and Day 10 suggested that steady state was reached on Day 6 (2 days after initiation of multiple dosing) (Data are not shown).
Fig. 2.
Mean plasma concentrations of dotinurad after multiple doses in Cohort B (0–72 h postdose on Day 10); PK analysis set: a linear scale and b semi-logarithmic scale. Error bars indicate standard deviation. PK pharmacokinetic
A summary of the PK parameters of dotinurad following multiple oral doses is shown in Table 4. After a single dose on Day 1 and multiple once-daily doses for 7 days from Day 4 to Day 10 at 4 mg of dotinurad, the mean AUC0–τ on Day 10 was 4470 ± 762 ng·h/mL and was almost equal to the mean AUC0–inf on Day 1. The mean accumulation ratios based on AUC (Rac(AUC0–24h)) and Cmax (Rac(Cmax)) were 1.13 ± 0.121 and 1.09 ± 0.185, respectively, suggesting that accumulation was minimal. Other parameters (CL/F, Vz/F, t½) were consistent with those following the single dose of dotinurad 4 mg on Day 1.
Table 4.
Pharmacokinetic parameters after multiple once-daily oral doses of dotinurad (pharmacokinetic analysis set)
| Pharmacokinetic parameter | Cohort B Dotinurad 4 mg, N = 10 |
|---|---|
| AUC0–τ, ng·h/mL | 4470 ± 762 |
| Css,max, ng/mL | 397 ± 69.4 |
| Css,min, ng/mL | 65.4 ± 22.1 |
| Css,av, ng/mL | 186 ± 31.8 |
| tss,max, h | 3.00 (2.00–6.00) |
| t½, h | 10.1 ± 1.72 |
| CLss/F, L/h | 0.923 ± 0.183 |
| Vz/F, L | 13.2 ± 1.64 |
| Rac(AUC0–24h) | 1.13 ± 0.121 |
| Rac(Cmax) | 1.09 ± 0.185 |
Data are shown as mean ± SD except tss,max; for tss,max, median (min–max) is shown
AUC0–τ area under the concentration–time curve over the dosing interval on multiple dosing, CLss/F apparent total clearance following oral administration at steady state, Cssav average steady-state concentration, Cssmax maximum observed concentration at steady state, Cssmin minimum observed concentration at steady state, Rac(AUC0–24h) accumulation ratio for area under the concentration–time curve from 0 to 24 h, Rac(Cmax) accumulation ratio for maximum observed concentration, t½ terminal elimination phase half-life, tssmax time at which the highest drug concentration occurs at steady state, Vz/F apparent volume of distribution at terminal phase
Safety
Four of 26 (15.4%) subjects, including 2/8 (25.0%) subjects who received a single dose of dotinurad 1 mg (Cohort A) and 2/10 (20.0%) subjects who received single and multiple doses of dotinurad 4 mg (Cohort B), experienced at least 1 TEAE during this study. Of these, 2/8 (25.0%) subjects who received a single dose of dotinurad 1 mg experienced drug-related TEAEs (alanine aminotransferase increased and blood triglycerides increased in one subject each). All the TEAEs were mild and resolved without any treatment. No fatal TEAE, serious TEAE, or TEAE leading to discontinuation of study drug was reported. No dose-dependent TEAEs were observed (Table 5).
Table 5.
TEAEs by dose and severity
| System organ class Preferred term |
Severity | Cohort A Dotinurad 1 mg, N = 8 |
Cohort B Dotinurad 4 mg, N = 10 |
Cohort C Dotinurad 10 mg, N = 8 | Total, N = 26 |
|---|---|---|---|---|---|
| Number of subjects with at least one TEAE | Any | 2 (25.0) | 2 (20.0) | 0 | 4 (15.4) |
| Mild | 2 (25.0) | 2 (20.0) | 0 | 4 (15.4) | |
| Moderate | 0 | 0 | 0 | 0 | |
| Severe | 0 | 0 | 0 | 0 | |
| Alanine aminotransferase increased | Mild | 1 (12.5)a | 0 | 0 | 1 (3.8) |
| Blood bilirubin increased | Mild | 0 | 1 (10.0) | 0 | 1 (3.8) |
| Blood triglycerides increased | Mild | 1 (12.5)a | 0 | 0 | 1 (3.8) |
| Body temperature increased | Mild | 0 | 1 (10.0) | 0 | 1 (3.8) |
Data are n (%)
TEAE treatment-emergent adverse event
aDetermined as drug-related TEAE
Discussion
This study evaluated the PK, safety, and tolerability of dotinurad in healthy Chinese subjects following single and multiple oral doses. The PK profile of dotinurad demonstrated rapid absorption and elimination, consistent across the evaluated dose range, with a short half-life leading to minimal accumulation. Steady state was reached 2 days of consecutive dosing, which could be attributed to the short half-life of dotinurad, as most of the drug is eliminated before the next dose (24 h post-dose), resulting in minimal accumulation.
Dotinurad exists mostly unchanged in the blood; its excretion pathway occurs predominantly through the urine as glucuronide and sulfate conjugates, with the involvement of multiple metabolic isoforms [25]. Considering the similarity in allele frequency of UGT and sulfotransferases among Asian ethnic groups [41–43], it is likely that any differences among Asian populations in these metabolic pathways are minimal. In addition, the demographics and baseline characteristics, including BMI and body weight, of healthy Chinese subjects in this study were comparable to those of Japanese cohorts in previous studies [31, 44], which may contribute to the observed similarity in pharmacokinetic profiles. Collectively, these factors (similar metabolic enzyme frequencies and body size) support our theory that there are no meaningful differences in the PK of dotinurad among Asian ethnic groups. In addition, at least six single-nucleotide variants in the UGT1A1 gene have been identified across four East Asian populations (i.e., Chinese, Japanese, Korean, and Taiwanese populations), indicating a genetic basis for similar drug metabolism [45].
Dotinurad had a good safety profile and was well-tolerated during the 7-day treatment course in the healthy Chinese adult subjects evaluated in this study. No new safety concerns were raised and the TEAEs reported in this study were consistent with the known safety profile of dotinurad.
This study has some limitations. Its generalizability is limited to healthy Chinese subjects, rather than patients with hyperuricemia or gout. On the basis of the previous finding that PK parameters do not significantly differ between patients with hyperuricemia or gout and healthy subjects [22, 23, 27–31, 38, 44], the PK data from this study are expected to be applicable to patients. Additionally, the results may not be applicable to other ethnic groups. Potential covariates of dotinurad PK, such as age, sex, BMI, body surface area, and renal function, were not evaluated using modeling approaches. Furthermore, pharmacodynamic assessments, including serum uric acid levels, were not performed; therefore, PK/pharmacodynamic analysis could not be conducted in this study.
Conclusions
Dotinurad exhibited a predictable and linear PK behavior across a dose range of 1–10 mg in healthy Chinese subjects. The PK profiles after multiple dosing were consistent with those observed after single dosing, indicating a predictable PK behavior under multiple administrations. Low accumulation ratios after multiple administrations indicated minimal drug accumulation. Dotinurad had a favorable safety profile and was well-tolerated during the 7-day treatment course in healthy Chinese subjects. These findings support the continued clinical development of dotinurad for the treatment of hyperuricemia and gout.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgments
We thank Michelle Belanger, MD, of Edanz (www.edanz.com), for providing medical writing support, which was funded by Eisai Co., Ltd., in accordance with Good Publication Practice guidelines (http://www.ismpp.org/gpp-2022).
Funding
This study was funded by Eisai Co., Ltd. Eisai Co., Ltd. was involved in study design, data collection, analysis, and interpretation of data.
Declarations
Conflicts of Interest
Y. Liu and Q. Chen have received honoraria (investigator fees) from Eisai Co., Ltd. H. Sun is an employee of Eisai China Inc. C. Cai, K. Kawamura, R. Kokan, and M. Nomoto are employees of Eisai Co., Ltd.
Ethics Approval and Consent to Participate
The protocol was approved by the ethics committee of Shanghai Xuhui Central Hospital (approval number 2022-002). The study was conducted in accordance with the Declaration of Helsinki and Chinese Good Clinical Practice guidelines and all applicable regulations. All study participants provided written informed consent. This study was registered at ClinicalTrials.gov under the identifier number NCT05278676.
Consent for Publication
Written consent for publication was obtained from all study participants.
Data Availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Code Availability
All analyses were conducted using standard software (SAS 9.4 and Phoenix WinNonlinTM 8.3.5). No custom code was used in this study, so code availability is not applicable.
Author Contributions
Conceptualization and methodology: Cuiyuan Cai, Kotomi Kawamura, Maiko Nomoto; investigation: Yun Liu, Qian Chen, Hui Sun, Rieko Kokan; formal analysis: Yun Liu, Qian Chen, Cuiyuan Cai, Maiko Nomoto; Writing—original draft and writing—review and editing: all authors. All authors read and approved the final version and agreed to submit the article for publication. All authors also confirm accountability for the accuracy and integrity of the work.
Footnotes
Cuiyuan Cai: Former employee of Eisai.
References
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Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.