Impact of Renal Impairment on the Pharmacodynamic and Pharmacokinetic Profiles of Epaminurad, a Novel Uric Acid Transporter 1 Inhibitor

ABSTRACT

Epaminurad, a novel uricosuric agent, exhibits potent inhibitory activity against the human uric acid transporter. This study aimed to investigate the effects of renal function and food intake on the pharmacokinetic, pharmacodynamic, and safety characteristics of 9 mg epaminurad. This study was designed as a phase 1, partially randomized, open‐label, oral administration, partial crossover trial. Participants were assigned to three groups based on renal function: normal (Group 1), moderate renal impairment classified as Stage 3a (Group 2) and Stage 3b (Group 3). Each group aimed to enroll 6–10 participants. Blood and urine samples were collected to evaluate the pharmacokinetics and pharmacodynamics of epaminurad. Safety assessments were also conducted throughout the study. A total of 27 participants completed the study, including 12 with normal renal function (Group 1) and 9 and 6 participants with moderate renal impairment (Groups 2 and 3), respectively. When a single 9 mg dose of epaminurad was administered under fasted conditions, the pharmacokinetic, pharmacodynamic, and safety profiles did not show clear differences among the renal function groups. Furthermore, no notable differences were observed in these profiles between the fasted and fed states. Patients with moderate renal impairment can receive (eGFR of 30–59 mL/min/1.73 m²) 9 mg epaminurad without dose adjustment, and the drug may be administered regardless of food intake.

Summary.

• What is the current knowledge on the topic?

  • ○
    Epaminurad, a novel uricosuric agent that selectively and potently inhibits human UA transporter 1, promotes renal excretion of UA.
  • ○
    Preclinical and early‐phase clinical studies have demonstrated its efficacy in lowering serum UA levels with a favorable safety profile.
• What question did this study address?

  • ○
    This study aimed to evaluate the impact of renal function and food intake on the pharmacokinetic, pharmacodynamic, and safety profiles of a single 9 mg dose of epaminurad in healthy individuals and patients with moderate renal impairment.
• What does this study add to our knowledge?

  • ○
    Epaminurad can be administered without dose adjustment in patients with moderate renal impairment (eGFR of 30–59 mL/min/1.73 m²) and irrespective of food intake, supporting its clinical flexibility and ease of use.
• How might this change clinical pharmacology and translational science?

  • ○
    The study provides evidence‐based dosing guidelines for patients with renal impairment and supports the use of early‐phase renal pharmacokinetic evaluation in drug development.
  • ○
    These findings may enhance clinical decision‐making and improve drug accessibility for patients with moderate renal function.

1. Introduction

Uric acid (UA) is the final product of purine metabolism [1], and can also be introduced into the body through dietary intake. Notably, approximately 90% of UA is excreted via the kidneys into the urine [2]. Under normal physiological conditions, serum UA concentrations are maintained within a specific range by homeostatic mechanisms. However, disruption of UA homeostasis can lead to serum UA levels exceeding 6.8 mg/dL, which is the saturation point at normal physiological temperatures and pH [3]. Persistent elevation above this threshold is defined as hyperuricemia [4]. In patients with hyperuricemia, monosodium urate crystals may accumulate in joints or soft tissues, potentially leading to gout [5].

Asymptomatic hyperuricemia is not recommended for drug therapy [6]. However, urate‐lowering therapy (ULT) is recommended to maintain serum UA levels below 6.0 mg/dL to prevent disease flares in patients with gout [7]. Medications used for ULT are broadly categorized into three groups: xanthine oxidase inhibitors (XOIs), uricases, and uricosurics [8].

XOIs, such as allopurinol and febuxostat, inhibit XO, the enzyme responsible for converting xanthine to UA during purine metabolism [9]. Allopurinol is considered the first‐line ULT. However, cases of Stevens‐Johnson syndrome and toxic epidermal necrolysis have been reported, particularly in individuals carrying the HLA‐B*5801 allele [10]. Febuxostat is not recommended as first‐line therapy in patients with a history of cardiovascular disease or recent cardiovascular events [11]. Recombinant uricases are therapeutic enzymes that convert UA into allantoin, a more water‐soluble compound [12]. Allantoin is approximately 5–10 times more soluble than UA, which facilitates its excretion via the kidneys. However, the gene encoding urate oxidase (UOX) exists as a nonfunctional pseudogene in mammals, particularly in humans [13]. As a result, alternatives such as non‐recombinant UOX or recombinant UOX derived from Aspergillus flavus have been employed in clinical practice [14].

Uricosurics, such as probenecid and benzbromarone, inhibit UA reabsorption and promote its excretion [15]. Human uric acid transporter 1 (hURAT1) is a key transporter involved in UA reabsorption in the renal proximal tubule [16, 17]. Probenecid is not recommended for patients with impaired renal function due to limited efficacy and an unclear dose–response relationship [18]. Benzbromarone can be used in patients with mild‐to‐severe renal impairment and is prescribed in several European countries and in Korea; however, it is not approved in the United States due to the risk of fatal hepatotoxicity [19]. Uricosuric agents are recommended as second‐line treatments when the target serum UA level is not achieved [20]. Therefore, there remains an unmet need for novel ULT agents.

Epaminurad is a novel uricosuric agent developed by JW Pharmaceutical Corporation. In nonclinical studies, epaminurad selectively inhibited hURAT1 more effectively than other transporters and demonstrated greater inhibition of UA reabsorption compared to benzbromarone. In vitro assays showed that the mitochondrial membrane potential IC₅₀ values for epaminurad ranged from 258 to 1830 μmol/L, whereas those for benzbromarone ranged from 1.11 to 9.34 μmol/L, indicating a lower risk of drug‐induced hepatotoxicity [21]. In addition, previous studies have shown that epaminurad is primarily metabolized by the UGT1A1 and UGT2C9 enzymes [22].

Preliminary studies in healthy participants showed that epaminurad was well‐tolerated with repeated doses of up to 10 mg for 7 days, and that serum UA levels decreased within 24 h after a single dose and remained reduced for up to 92 h following repeated dosing. The increase in urinary excretion of UA occurred primarily within the first 12 h. In addition, the pharmacodynamic (PD) and pharmacokinetic (PK) parameters of epaminurad exhibited dose‐proportional changes following single doses ranging from 1 to 30 mg and repeated doses from 1 to 10 mg [23].

This study aimed to evaluate the PD, PK, and safety profiles of epaminurad by comparing healthy individuals and patients with moderate renal impairment. The primary objectives were to determine whether dose adjustment is required in patients with moderate renal impairment and whether epaminurad can be administered regardless of dietary status.

2. Methods

2.1. Ethics Approval and Consent to Participate

The study was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable regulatory requirements to ensure the safety and rights of all participants. The study was registered at ClinicalTrials.gov (Identifier: NCT05198778) and was approved by the Ministry of Food and Drug, Republic of Korea. Institutional Review Board (IRB) approvals were also obtained from Chungbuk National University Hospital (IRB No. 2021‐09‐033) and Ajou University Hospital (IRB No. AJIRB‐MED‐CT1‐22‐092). Written informed consent was obtained from all participants prior to enrollment.

Participants were selected following screening and assessments based on predefined inclusion and exclusion criteria (Table S7). For patients with renal impairment, only those with stable chronic kidney disease, defined as no changes in renal function for at least 3 months prior to enrollment, were eligible. During the study, medications that were not expected to interact with epaminurad, such as XOIs, uricases, and uricosurics, including those acting on hURAT1, were permitted. In contrast, healthy participants were restricted from taking any medications, including over‐the‐counter drugs.

2.2. Design and the Study Drug

This was a phase 1, partially randomized, multicenter, open‐label, oral‐administration, partial crossover study. Participants were recruited and assigned to three groups based on their estimated glomerular filtration rate (eGFR), which was calculated using the Modification of Diet in Renal Disease equation. The eGFR was determined using the following formula: eGFR (mL/min/1.73 m²) = 186 × (serum creatinine)^{−1 .154} × (age)^{−0 .203} (×0.742 if female).

Group 1: Healthy participants with normal renal function (eGFR ≥ 90 mL/min/1.73 m²).

Group 2: Participants with Stage 3a moderate renal function (45 ≤ eGFR < 60 mL/min/1.73 m²).

Group 3: Participants with Stage 3b moderate renal function (30 ≤ eGFR < 45 mL/min/1.73 m²).

To achieve the study objectives with the minimum required sample size, 6 to 10 participants were enrolled per group, except for Group 1 (healthy participants), which comprised 12 participants. Participants in Group 1 were randomly allocated to different dosing orders using simple randomization.

The study comprised two parts: an assessment of renal function‐based differences (Study 1) and an evaluation of food effects (Study 2). Each group was recruited separately. Healthy participants (Group 1) received epaminurad under fasted and fed conditions in a two‐period crossover design. Although the order of administration (fasted or fed) was randomized, the fasted‐state data from Group 1 were used as a comparator in Study 1 for comparisons with participants with renal impairment, while both fasted and fed data were used in Study 2 to evaluate food effects.

In Study 1, all participants received a single 9 mg dose of epaminurad with 150 mL of water after a minimum 10‐h fast. In Study 2, Group 1 participants received a 9 mg dose of epaminurad with 150 mL of water under fasted and fed conditions in a crossover design, with a 1‐week washout period between administrations.

The study consisted of a screening period (Days −28 to −2), hospitalization period (Days −2 to 4), treatment period (Days 1 to 4), and follow‐up visits (Days 8 to 10).

2.3. PD Assessment

To evaluate the PD properties of epaminurad, blood samples were collected at the following time points: 24 h pre‐administration, immediately before administration (0 h), and at 2, 4, 6, 8, 10, 24, 48, and 72 h post‐administration for the measurement of serum UA and creatinine levels. For PD blood sampling, approximately 6 mL of whole blood was collected into SST tubes at each point.

Urine samples were collected over the following intervals: 24 h pre‐administration, and 0–4, 4–8, 8–12, 12–24, 24–48, and 48–72 h post‐administration. Each urine sample was collected using a urine bag and refrigerated at 4°C during the collection period. Urine volume was measured by weight, assuming a density of 1 g/mL. A 10 mL aliquot was separated for analysis at each time point.

PD analyses were conducted by the Department of Laboratory Medicine at each participating institution, which were designated as the specimen analysis laboratories.

The PD evaluation variables included the area under the effect curve (AUEC) of serum UA levels, fractional excretion of UA (FEUA), and urinary UA excretion. AUEC was calculated using the trapezoidal rule, and FEUA was determined using the following formula: FEUA (%) = UA clearance/creatinine clearance × 100.

2.4. PK Assessment

The PK properties of epaminurad were evaluated by analyzing plasma and urine samples collected over a 72‐h period following drug administration.

For plasma PK analysis, blood samples were collected at the following time points: pre‐administration (0 h), and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 h post‐administration. Approximately 8 mL of whole blood was collected into EDTA‐K2 tubes at each time point. The samples were centrifuged at 3000 rpm for 10 min at 4°C, and the resulting plasma was transferred to Eppendorf tubes and stored at −70°C.

For urine PK analysis, samples were collected over the following intervals: 0–4, 4–8, 8–12, 12–24, 24–48, and 48–72 h post‐administration. In addition, a 0‐h pre‐administration spot urine sample was collected for baseline measurement. These time points were aligned with those used for PD urine sampling. However, unlike PD sampling, which included a 24‐h pre‐dose collection, PK analysis required only a 0‐h spot sample before dosing. After measuring the urine volume, a 1 mL portion was transferred into the Eppendorf tube and stored at −70°C for PK analysis.

Plasma samples were pretreated using a protein precipitation method and analyzed by liquid chromatography (Shimadzu Prominence UFLC, Shimadzu, Japan) coupled with tandem mass spectrometry (TQ5500(2), SCIEX, USA). Data acquisition and processing were performed using Analyst software version 1.6.3 (SCIEX). Regression analysis was conducted using a 1/x² weighting factor.

For plasma samples, the calibration curve range was 1–1000 ng/mL with a correlation coefficient ≥ 0.9950. Assay accuracy ranged from 93.3% to 103.0%, with coefficients of variation (CVs) between 1.0% and 4.3%. For quality control (QC) samples, accuracy ranged from 98.8% to 104.6%, with CVs of 2.5% to 5.8%. For urine samples, the calibration curve range was 1–500 ng/mL with a correlation coefficient ≥ 0.9950. Assay accuracy ranged from 97.7% to 102.0%, with CVs between 1.6% and 4.5%. For QC samples, accuracy ranged from 97.5% to 99.3%, with CVs of 2.7% to 5.1%.

Plasma PK analysis was performed using concentration data processed in Phoenix WinNonlin version 8.3 (Certara, NJ, USA). Non‐compartmental analysis was conducted using the linear‐up/log‐down method. The PK parameters assessed included maximum plasma concentration (C _max), time to reach C _max (T _max), area under the plasma concentration‐time curve from time 0 to the last quantifiable concentration (AUC_0‐t), elimination half‐life (t _1/2) following single‐dose administration, apparent clearance (CL/F), and apparent volume of distribution (Vd/F).

For the urinary PK evaluation, the amount of unchanged epaminurad excreted in urine during each time interval (Ae_t), the fraction of the administered dose excreted unchanged in urine (fe_t), and renal clearance (CL_R) were calculated. Ae_t was calculated by multiplying the measured urine concentration by the corresponding volume. fe_t was calculated as the ratio of Ae_t to the administered dose. CL_R was calculated by dividing Ae_t by the plasma AUC over the same time interval.

2.5. PK–PD Relationship

PK–PD relationship analysis was performed to assess the correlation between C _max or AUC_0‐t and PD parameters—AUEC of serum UA, FEUA, and urinary UA excretion—over the 0–24 and 0–72 h intervals. Scatter plots were generated for visualization, and p‐values were derived using simple linear regression and Pearson correlation analysis.

Additionally, a univariate linear regression analysis was conducted to examine the association between FEUA (0–24 h) and demographic and PK variables.

2.6. Safety Assessment

Safety was evaluated through continuous monitoring of adverse events (AEs) throughout the study period, along with the recording of all AEs and concomitant medications (CMs). Pre‐specified safety assessments included clinical laboratory tests, vital signs, physical examinations, and 12‐lead electrocardiography.

2.7. Statistical Analysis

Statistical analyses were performed using commercial software, SAS Analytics Pro version 9.4 (SAS Institute Inc., Cary, NC, USA). Group differences were assessed using the Kruskal‐Wallis test or Wilcoxon rank‐sum test, depending on the data distribution, with a significance level of 5%.

For comparison of PD effects between groups, geometric mean ratios (GMRs) and corresponding 90% confidence intervals (90% CIs) were calculated for each parameter over the 0–24 and 0–72 h intervals.

For PK analysis, descriptive statistics were calculated for each parameter within groups, including changes from baseline at each time point. Additionally, GMRs and 90% CIs were calculated for C _max and AUC_0‐t.

In accordance with relevant regulatory guidance [24, 25, 26], using GMRs and 90% CIs is recommended for between‐group comparisons of PK and PD parameters. In this study, the calculated GMRs and their 90% CIs were assessed to explore whether the values fell within the conventional range often used in bioequivalence studies (0.80–1.25) or suggested clinically meaningful differences. The comparisons were made against control groups, which included healthy participants with normal renal function under fasted conditions in both Study 1 and Study 2. Specifically, groups classified by renal function in Study 1 and the fed group with normal renal function in Study 2 were considered as test groups. However, as this study was exploratory rather than hypothesis‐driven, GMRs and 90% CIs were interpreted according to conventional statistical principles [27].

3. Results

3.1. Participants

A total of 28 participants were enrolled across the two studies: 12 in Group 1, 10 in Group 2, and 6 in Group 3. One participant in Group 2 withdrew consent prior to dosing. Thus, a total of 27 participants completed the study after receiving the 9 mg dose of epaminurad (Figure S1, Figure S2). Age was the only demographic characteristic identified as statistically different among the groups (Table S1).

3.2. Pharmacodynamic

A total of 27 participants were included in the analysis. Two participants from Group 1 experienced partial urine loss: one during the fasted state and the other during the fed state. As a result, urine‐based PD analysis included 26 participants, whereas the blood‐based PD analysis included all 27 participants.

After a single 9 mg dose of epaminurad under fasted conditions, serum UA levels decrease until 12 h post‐administration and then begin to increase (Figure 1a). Baseline serum UA levels were 5.28 ± 1.37 mg/dL in Group 1, 6.67 ± 2.01 mg/dL in Group 2, and 7.20 ± 1.51 mg/dL in Group 3 (Table S2). The AUEC of serum UA from 0 to 72 h showed GMRs (90% CIs) of 1.5649 (1.2422–1.9715) in Group 2 and 1.6964 (1.3055–2.2043) in Group 3, compared with healthy controls (Table 1).

FIGURE 1.

Mean time–course profiles of (a) serum uric acid concentration, (b) FEUA, and (c) urinary uric acid excretion by renal function group following a single 9 mg oral dose of epaminurad under fasted conditions (Study 1).

TABLE 1.

Geometric mean and geometric mean ratio [90% confidence interval] of pharmacodynamic parameters following a single 9 mg oral dose of epaminurad.

	Geometric mean		GMR (90% CI)
	Group 2	Group 1 a
Serum uric acid AUEC (h*mg/dL)
0–24 h	113.4429	64.2062	1.7669 (1.3519–2.3092)
0–72 h	369.2227	235.9217	1.5649 (1.2422–1.9715)
FEUA (%)
0–24 h	14.8872	12.8816	1.1557 (0.6931–1.9273)
0–72 h	9.4536	8.5318	1.1080 (0.7427–1.6533)
Urinary excretion of uric acid (mg)
0–24 h	585.1101	555.9064	1.0525 (0.7042–1.5730)
0–72 h	1286.5249	1410.5007	0.9121 (0.6678–1.2457)

	Geometric mean		GMR (90% CI)
	Group 3	Group 1 a
Serum uric acid AUEC (h*mg/dL)
0–24 h	124.8733	64.2062	1.9449 (1.4356–2.6345)
0–72 h	400.2142	235.9217	1.6964 (1.3055–2.2043)
FEUA (%)
0–24 h	17.1397	12.8816	1.3306 (0.7470–2.3703)
0–72 h	11.3896	8.5318	1.3350 (0.8497–2.0974)
Urinary excretion of uric acid (mg)
0–24 h	552.3600	555.9064	0.9936 (0.6312–1.5641)
0–72 h	1251.7527	1410.5007	0.8875 (0.6241–1.2619)

	Geometric mean		GMR (90% CI)
	Fed state of Group 1	Group 1 a
Serum uric acid AUEC (h*mg/dL)
0–24 h	57.9975	64.2062	0.9032 (0.8720–0.9356)
0–72 h	222.8057	235.9217	0.9443 (0.9232–0.9660)
FEUA (%)
0–24 h	16.2387	12.2583	1.3247 (1.0070–1.7425)
0–72 h	9.6225	8.2548	1.1657 (1.0484–1.2962)
Urinary excretion of uric acid (mg)
0–24 h	687.7325	548.9460	1.2527 (0.9766–1.6069)
0–72 h	1642.0488	1408.2457	1.1660 (1.0419–1.3049)

Abbreviations: AUEC, area under the effect curve; CI, confidence interval; FEUA, fractional excretion of uric acid; GMR, geometric mean ratio.

^a The control group represents the fasted state of Group 1.

FEUA levels and urinary excretion of UA demonstrated overall similar profiles across the healthy and renally impaired groups (Figure 1b,c). The GMRs (90% CIs) for FEUA_0‐72 were 1.1080 (0.7427–1.6533) in Group 2 and 1.3350 (0.8497–2.0974) in Group 3; for urinary excretion of UA, the values were 0.9121 (0.6678–1.2457) and 0.8875 (0.6241–1.2619), respectively (Table 1). As the study involved a small sample size and substantial inter‐individual variability, the observed differences are difficult to interpret as statistically meaningful. Consistently, 90% CIs of the GMRs included 1, and the corresponding p‐values were > 0.05 (Table S2), further supporting the absence of clear differences between groups.

3.3. Pharmacokinetic

PK analysis was conducted on 27 participants. As with the PD analysis, blood PK analysis included all 27 participants, while urine PK analysis included 26 participants.

The median T _max was 1.00 h for Groups 1 and 2, and 0.50 h for Group 3, showing a generally comparable absorption profile across groups (Figure 3a). Accordingly, differences in C _max and AUC_0‐t did not appear clinically meaningful (Table 3).

FIGURE 3.

Mean plasma concentration‐time profiles of epaminurad (a) by renal function group under fasted conditions (Study 1), and (b) by dietary condition (fasted vs. fed) in healthy participants (Study 2).

TABLE 3.

Summary of plasma and urine pharmacokinetic parameters by renal function group following a single 9 mg oral dose of epaminurad under fasted conditions (study 1).

	Group 1 (n = 12) a	Group 2 (n = 9)	Group 3 (n = 6)
AUC0‐t (h*ng/mL)	6202.39 ± 1318.59	5345.08 ± 1477.38	6235.49 ± 779.16
C max (ng/mL)	775.09 ± 103.32	733.20 ± 170.70	794.45 ± 69.25
T max (h)	1.00 [0.50–2.50]	1.00 [0.50–4.00]	0.50 [0.50–1.00]
t 1/2 (h)	7.26 ± 1.01	6.40 ± 1.35	7.98 ± 1.40
Vd/F (L)	15.52 ± 3.09	16.44 ± 4.72	16.80 ± 4.10
CL/F (L/h)	1.50 ± 0.34	1.85 ± 0.74	1.45 ± 0.17
fet (%)	0.36 ± 0.07	0.20 ± 0.04	0.19 ± 0.12
Aet (mg)	0.03 ± 0.01	0.02 ± −	0.02 ± 0.01
CLR (mL/h)	5.57 ± 1.99	3.70 ± 1.52	2.79 ± 1.72

Note: Data presented as mean ± standard deviation, except for T _max, which is presented as median [min—max].

Abbreviations: Ae_t, cumulative amount of urinary excretion up to the last time point of urine sampling; AUC_0‐t, area under the curve; CL/F, apparent total clearance; CL_R, renal clearance of the drug from plasma; C _max, maximum plasma concentration; fe_t, fraction of the administered drug excreted into the urine; t _1/2, terminal elimination half‐life; T _max, time to reach maximum plasma concentration; Vd/F, apparent volume of distribution.

^a fe_t, Ae_t, CL_R were measured in 11 participants.

The GMRs (90% CIs) of C _max and AUC_0‐t for Groups 2 and 3, relative to the healthy group, were 0.9247 (0.8010–1.0675) and 0.8417 (0.6977–1.0153), and 1.0302 (0.8754–1.2124) and 1.0197 (0.8243–1.2614), respectively (Table 2).

TABLE 2.

Geometric mean and geometric mean ratio [90% confidence interval] of pharmacokinetic parameters following a single 9 mg oral dose of epaminurad.

	Geometric mean		GMR (90% CI)
	Group 2	Group 1 a
C max (ng/mL)	710.8996	768.7542	0.9247 (0.8010–1.0675)
AUC0‐t (h*ng/mL)	5114.7121	6076.8458	0.8417 (0.6977–1.0153)

	Geometric mean		GMR (90% CI)
	Group 3	Group 1 a
C max (ng/mL)	791.9942	768.7542	1.0302 (0.8754–1.2124)
AUC0‐t (h*ng/mL)	6196.4833	6076.8458	1.0197 (0.8243–1.2614)

	Geometric mean		GMR (90% CI)
	Fed state of Group 1	Group 1 a
C max (ng/mL)	677.3024	768.7542	0.8810 (0.8294–0.9359)
AUC0‐t (h*ng/mL)	5941.4552	6076.8458	0.9777 (0.9276–1.0305)

Abbreviations: AUC_0‐t, area under the plasma concentration‐time curve from time 0 to the last quantifiable concentration; CI, confidence interval; C _max, maximum plasma concentration; GMR, geometric mean ratio.

^a The control group represents the fasted state of Group 1.

The mean ± SD values of CL_R were 5.57 ± 1.99, 3.70 ± 1.52, and 2.79 ± 1.72 mL/h for Groups 1, 2, and 3, respectively. The corresponding CL/F values were 1.50 ± 0.34, 1.85 ± 0.74, and 1.45 ± 0.17 L/h. The observed t _1/2 values were also comparable across groups, with values of 7.26, 6.40, and 7.98 h for Groups 1, 2, and 3, respectively. The cumulative Ae_t up to 72 h post‐dose was below 0.03 mg in all groups, and fe_t was below 0.36% (Table 3).

3.4. Food Effects on Healthy Participants

Following a single 9 mg dose of epaminurad under fasted and fed conditions, serum UA levels (Figure 2a), FEUA (Figure 2b), and urinary excretion of UA (Figure 2c) exhibited comparable patterns.

FIGURE 2.

Mean time–course profiles of (a) serum uric acid concentration, (b) FEUA, and (c) urinary uric acid excretion under fasted and fed conditions in healthy participants following a single 9 mg oral dose of epaminurad (Study 2).

The GMRs (90% CIs) for AUEC of serum UA, FEUA, and urinary UA excretion, comparing the fasted to the fed state, were 0.9443 (0.9232–0.9660), 1.1657 (1.0484–1.2962), and 1.1660 (1.0419–1.3049), respectively (Table 1).

Serum UA levels remained within the conventional bioequivalence range regardless of dietary status, whereas FEUA and urinary UA excretion were approximately 17% higher in the fed state compared to the fasted state.

From the PK perspective, key parameters were similar between the fed and fasted states, with C _max and AUC_0‐t values falling within the conventional bioequivalence range. The GMRs (90% CIs) for C _max and AUC_0‐t were 0.8810 (0.8294–0.9359) and 0.9777 (0.9276–1.0305), respectively (Table 2). The T _max was delayed (Figure 3b), with a median of 1.00 h in the fasted state and 3.00 h in the fed state (Table S4).

3.5. PK–PD Relationship

PK–PD analysis revealed a statistically significant correlation between C _max and the AUEC of serum UA (Figure 4). Although visual trends were observed for other PK–PD parameters (Figure S3), statistical significance was not achieved, which was likely attributable to the small sample size and inter‐individual variability.

FIGURE 4.

Relationship between epaminurad C _max and serum uric acid AUEC: (a) AUEC_0‐24h, and (b) AUEC_0‐72h (p‐value via Pearson method).

Additional univariate linear regression identified sex and age as significant covariates of FEUA over the 0–24 h period, while most other PK parameters were not significantly associated (Table S5).

3.6. Safety

Safety was assessed in 27 participants. A total of four AEs were reported in three participants: two in the renal impairment group and one in the healthy group. In the renal impairment group, the reported AEs were increased blood creatinine and papular rash. In the healthy group, two AEs—abdominal pain and lower abdominal pain were assessed as adverse drug reactions (ADRs). All AEs were mild in severity (Table S6). CMs were administered for the AEs in participants with renal impairment, whereas no treatment was required for ADRs in the healthy participants.

4. Discussion

FEUA represents the proportion of filtered UA that is excreted in the urine and is typically less than 10% in healthy individuals [28]. It serves as an indicator of renal UA excretion efficiency. In this study, FEUA from 0 to 72 h post‐dose was 8.82%, 10.90%, and 13.46% in Groups 1, 2, and 3, respectively. Although urinary UA excretion was numerically higher in the renal impairment groups, the differences were relatively modest, likely due to elevated baseline serum UA levels (Table S2).

Uricosurics may be limited by adverse effects such as renal and hepatic impairment, and their efficacy may be reduced in patients with low eGFR [29]. A phase 3 study of lesinurad—a uricosuric agent previously approved in the United States, similar to epaminurad—reported a less pronounced reduction in serum UA levels in patients with moderate renal impairment compared to healthy individuals, which was considered clinically acceptable at the time [30]. Likewise, in this study, epaminurad demonstrated comparable PD characteristics between patients with moderate renal impairment and healthy participants.

In a previous study [31], a single 200 mg dose of lesinurad in healthy adults increased FEUA to a peak of 21.8% at 6 h post‐dose, returning to baseline levels at 24 h. Similarly, in this study, a single 9 mg dose of epaminurad in healthy participants increased FEUA to a peak of 21.1% at 12 h post‐dose, followed by a return to baseline levels around 24 h. Healthy participants excreted nearly baseline levels of urinary UA for up to 24 h post‐dose, whereas participants with renal impairment excreted greater‐than‐baseline levels (Table S2). Consequently, the differences between groups were small and not regarded as clinically meaningful. Although reduced eGFR is generally expected to result in lower urinary excretion, this finding warrants further discussion. This outcome is likely attributable to higher baseline serum UA concentrations in the renal impairment groups, which may have offset the reduced filtration associated with lower eGFR, thereby maintaining urinary UA excretion. Furthermore, inhibition of URAT1 by epaminurad reduces tubular reabsorption, thereby facilitating urinary UA excretion. As a result, despite reduced renal function, participants with renal impairment exhibited similar total urinary UA excretion compared to healthy participants. A comparable mechanism has been observed in the treatment of type 2 diabetes mellitus, where SGLT‐2 inhibitors act at the level of the kidney, resulting in greater urinary glucose excretion in patients than in healthy individuals [32].

Most PK parameters showed no clear differences according to renal function status. In addition, all groups exhibited a fe_t of > 0.36% (Table 3), indicating that epaminurad is primarily eliminated via hepatic metabolism rather than renal excretion, which is consistent with previously reported findings. This finding aligns with reports for similar URAT1 inhibitors such as verinurad, which has a urinary excretion rate of 2% [33]. Although CL_R was reduced in the renal impairment groups (Groups 2 and 3) compared to Group 1, the CL/F remained comparable across all groups, regardless of renal function (Table 3).

Elimination t _1/2 was comparable between healthy individuals and patients with moderate renal impairment (Table 3). Notably, PD changes, including reductions in serum UA concentrations, increases in FEUA, and increases in urinary UA excretion, were observed from 12 to 24 h post‐dose compared to baseline (Figure 1). Thereafter, values either returned to baseline or fell below baseline levels, likely due to homeostatic regulation. These findings collectively support the feasibility of maintaining once‐daily dosing of epaminurad across individuals with normal to moderately impaired renal function.

Results from Study 2, which evaluated the influence of food intake, showed higher average FEUA and urinary UA excretion in the fed state compared to the fasted state (Table S3). This effect may reflect both delayed absorption and, more importantly, the influence of the high‐fat meal, particularly on FEUA and urinary UA excretion.

Under fed conditions, the C _max was within the conventional bioequivalence range; however, it was approximately 12% lower on average compared with that in the fasted state. Additionally, the median T _max of epaminurad was delayed. These findings may be attributed to delayed gastric emptying and altered absorption rate related to the drug's lipophilicity [34], suggesting no meaningful difference in overall drug exposure between fed and fasted states.

Following epaminurad administration, urinary UA excretion increased; however, no crystallization or stone formation was reported. Although elevated urinary UA is recognized as a theoretical concern associated with uricosuric agents, no related safety issues were identified in this study. Furthermore, no renal‐related AEs were observed during the end‐of‐study assessments, and eGFR values remained stable compared to baseline. Given the known hepatotoxicity risk associated with benzbromarone, another uricosuric agent with similar mechanisms of action, hepatic safety parameters were carefully monitored before and after epaminurad administration. No hepatotoxic AEs or clinically significant abnormalities in liver function tests were observed.

In this study, the PD, PK, or safety profiles of epaminurad did not show clear differences across renal function groups. These findings suggest that epaminurad can be administered without dose adjustment in patients with moderate renal impairment to promote UA excretion. Furthermore, the PD and PK profiles of epaminurad remained consistent regardless of food intake, and no differences in safety outcomes were identified between fed and fasted states. While allopurinol is approved for administration with food to reduce gastrointestinal side effects, epaminurad can be prescribed independently of meal timing.

This study has some limitations. First, as uricosuric agents are generally recommended as adjunctive therapies to standard ULT [35], further investigation is warranted to evaluate the PD, PK, and safety profiles of epaminurad when used in combination with existing ULT agents. Second, this study did not include patients with gout. Since the PD, PK, and safety characteristics may differ in the gout population, future studies specifically targeting patients with gout are necessary to validate these findings. Third, the observed correlation between C _max and PD outcomes should be interpreted with caution, as the small sample size may have limited the detection of potential associations with other PK parameters such as AUC. Further studies with larger populations are needed to confirm the robustness of this PK–PD relationship.

The results of this study suggest that a single 9 mg dose of epaminurad can be administered once daily without dose adjustment, regardless of food intake, in patients with moderate renal impairment. This supports the use of epaminurad without dose adjustment in patients with normal renal function and those with moderate renal impairment. Also, these findings provide supportive evidence for the continued clinical development of epaminurad as a novel uricosuric agent.

Author Contributions

S.Y.P. and J.G.H. wrote the manuscript. J.G.H., S.K.C., and M.K.P. designed the research. S.Y.P., J.G.H., S.K.C., and M.K.P. performed the research. S.Y.P. and J.G.H. analyzed the data. All authors participated in the data interpretation and manuscript revision for important intellectual content.

Conflicts of Interest

Min Kyu Park and Jun Gi Hwang are professors of Chungbuk National University. The other authors declare no conflicts of interest.

Supporting information

Data S1