What diseases does Dotinurad treat?

Overview of Dotinurad

Dotinurad is a small molecule drug developed as a selective urate reabsorption inhibitor (SURI) that belongs to the class of uricosuric agents. Its chemical structure, characterized by a benzothiazole core with dichloro and hydroxyl substituents, confers high potency and selectivity for inhibiting the urate transporter 1 (URAT1), which is primarily expressed in the renal proximal tubules. This specificity is achieved without significant inhibition of other urate secretion transporters such as ATP-binding cassette subfamily G member 2 (ABCG2) and organic anion transporters (OAT1/3). Its pharmacological profile is marked by linear dose-exposure relationships, favorable pharmacokinetics in various populations (including healthy subjects, those with mild or moderate renal impairment, or hepatic impairment), and a once-daily dosing regimen that simplifies treatment adherence. The molecule is predominantly excreted as glucuronide and sulfate conjugates, ensuring that its renal elimination is efficient and that dose adjustments are often not required even in special populations.

Mechanism of Action 
Dotinurad functions by selectively inhibiting URAT1, an essential transporter responsible for the reabsorption of uric acid from the renal tubule back into the bloodstream. By blocking URAT1, dotinurad increases the fractional excretion of uric acid, thereby effectively lowering serum uric acid levels. This mechanism not only addresses elevated serum uric acid levels but also facilitates the dissolution of monosodium urate crystals deposited in joints and other tissues—one of the main causative factors of gout. Importantly, its selectivity minimizes the risk of interfering with other renal excretion pathways, which contributes to its overall safety profile and makes it particularly attractive in patients who may have background complications such as mild renal impairment.

Diseases Treated by Dotinurad

Primary Indications 
Dotinurad is primarily indicated for the treatment of gout and hyperuricemia. Gout is an inflammatory arthritis characterized by episodic attacks of severe pain, swelling, and redness in the joints due to the deposition of monosodium urate crystals. By effectively lowering serum uric acid levels, dotinurad helps prevent the formation of these crystals and, in turn, reduces the frequency and severity of gout attacks. Clinical trials and regulatory approvals in Japan have established the efficacy of dotinurad in this domain. Specifically, it was approved in Japan on January 23, 2020, as a once-daily oral therapy for patients with gout and hyperuricemia, demonstrating a significant reduction in serum uric acid concentration. 
In addition to managing acute gouty arthritis, dotinurad can also be employed in the long-term management of hyperuricemia—whether or not the patient presents with overt gout. Hyperuricemia itself is a metabolic disorder defined by elevated serum uric acid levels, which may lead not only to gout but also to other complications if left untreated. Consistent with Japanese guidelines, management of hyperuricemia aims to maintain serum uric acid levels below 6.0 mg/dL to avoid further complications such as the formation of urate crystals in extra-articular tissues. Clinical studies have shown that dotinurad is effective in steadily lowering serum uric acid with long-term administration reaching target levels in a significant proportion of patients.

Off-label Uses 
While the principal approved indication for dotinurad is gout and hyperuricemia, there is emerging interest in its potential off-label applications. According to regulatory and news reports from clinical development programs, dotinurad might hold promise for other hyperuricemic conditions associated with comorbidities. For example, some data suggest that dotinurad’s potent URAT1 inhibition and consequent serum uric acid lowering effect may be beneficial in patients with chronic kidney disease (CKD) where hyperuricemia is a risk factor for progression of renal dysfunction. Given that many patients with CKD have compromised urate excretion, the safety profile of dotinurad in mild-to-moderate renal impairment has been encouraging. In this regard, its use as an adjunct therapy to slow kidney function decline through better management of serum uric acid levels is under exploration. 
Furthermore, there is an indication from industry news that dotinurad could have potential benefits in managing conditions such as heart failure. Specifically, the drug is being considered for hyperuricemic indications that extend to heart failure, where elevated uric acid levels may worsen cardiovascular outcomes. Because gout, CKD, and heart failure often coexist—particularly in older patients—dotinurad might one day be utilized in a multi-pronged approach targeting the complex interplay between hyperuricemia and cardiovascular or renal dysfunction. Although these off-label uses require further evidence from well-designed clinical trials, they currently represent promising areas for future research and potential expansion of the therapeutic indication for dotinurad.

Clinical Efficacy and Safety

Clinical Trial Results 
Multiple clinical trials have evaluated the efficacy and safety profile of dotinurad, contributing significantly to the understanding of its therapeutic value in gout and hyperuricemia. In pivotal phase 2 and phase 3 clinical trials, dotinurad demonstrated a robust reduction in serum uric acid levels in patients with hyperuricemia with or without gout. In one confirmatory randomized, multicenter, double-blind, placebo-controlled trial, patients treated with escalating doses of dotinurad (ranging from 0.5 mg to 4 mg) exhibited a dose-dependent reduction in serum uric acid concentrations. At the highest dose (4 mg), the serum uric acid reduction reached over 60% compared to baseline, and virtually 100% of patients achieved target serum uric acid levels (≤6 mg/dL). 
Additionally, further exploratory trials have established that dotinurad provides comparable efficacy to other established urate-lowering agents such as benzbromarone and febuxostat. In a head-to-head non-inferiority trial, dotinurad demonstrated a percent change in serum uric acid level from baseline that was statistically non-inferior to that achieved with febuxostat, with a mean difference of only a couple of percentage points. The consistency of dotinurad’s serum uric acid lowering effect has been observed across various patient subgroups, including patients with renal or hepatic impairment, as the pharmacokinetics and pharmacodynamics of dotinurad are largely unaffected by mild-to-moderate dysfunction in these organs. 
Moreover, post hoc analyses from clinical trials have provided insights into the dynamics of urinary uric acid excretion. Initial increases in urinary uric acid concentration observed with the initiation or dose increase of dotinurad tend to normalize over time, which underscores the importance of patient monitoring in the early phases of therapy. Overall, these trials confirm that dotinurad’s efficacy in maintaining target serum uric acid levels is maintained over long-term treatment periods, which is essential for preventing both acute and chronic gout-related complications.

Common Side Effects 
Dotinurad is generally well tolerated. The safety profile in clinical trials has been comparable to that of other uricosuric agents, with most adverse events being mild or moderate in severity. The most commonly reported side effects include mild gastrointestinal disturbances such as nausea, abdominal discomfort, and, infrequently, diarrhea. Some patients may also experience transient increases in urinary uric acid excretion, which can potentially lead to urinary tract discomfort; however, this effect typically normalizes with continued treatment. 
Importantly, liver-related adverse drug reactions have been observed less frequently with dotinurad compared to other uricosuric drugs such as benzbromarone; this is a significant consideration given the liver toxicity concerns associated with some alternatives. Additionally, the incidence of gouty arthritis flare-ups, which are common during the initiation of urate-lowering therapy, did not show a significant increase in patients taking dotinurad, indicating a favorable risk profile. Overall, the incidence of adverse events did not increase in a dose-dependent manner and was within the acceptable range for a drug used to manage chronic conditions such as gout and hyperuricemia.

Comparison with Other Treatments

Advantages over Other Medications 
One of the most significant advantages of dotinurad over alternative urate-lowering therapies lies in its high selectivity and potency toward URAT1 inhibition. Unlike older uricosuric drugs such as benzbromarone or probenecid, which can have broader effects on various renal transporters and cause unpredictable drug–drug interactions, dotinurad’s selective mechanism minimizes its interference with other urate secretion transporters such as ABCG2 and OAT1/3. This selectivity not only improves its safety profile by reducing off-target effects but also allows for a more significant reduction in serum uric acid levels with relatively lower doses. 
In randomized trials, dotinurad demonstrated non-inferiority when compared to febuxostat—a widely used xanthine oxidase inhibitor—with an efficacy that is comparable in lowering serum uric acid levels while potentially offering fewer safety concerns related to cardiovascular risk, as febuxostat carries a black box warning for increased risk of cardiovascular death in some populations. Additionally, dotinurad’s once-daily dosing regimen and linear pharmacokinetics facilitate ease of use and adherence, which is essential in the management of a chronic disease like gout. 
The drug’s favorable pharmacodynamic profile has also been confirmed in special populations such as elderly patients and those with mild-to-moderate renal or hepatic impairment, which positions dotinurad as a versatile option in patients who might not tolerate other urate-lowering therapies due to comorbid conditions. From a clinical outcomes perspective, the achievement of target serum uric acid levels with dotinurad in both short-term and long-term studies suggests that it could help reduce the frequency of acute gout attacks and slow or prevent long-term joint and renal damage.

Limitations and Considerations 
Despite its advantages, several considerations must be taken into account when administering dotinurad. For instance, as with most uricosuric agents, the initial phase of therapy may be associated with a transient increase in urinary uric acid excretion, necessitating monitoring to prevent crystal formation in the urinary tract or potential nephrolithiasis, especially in patients with low urine volume. 
Moreover, while dotinurad does not require dose adjustment in mild-to-moderate renal impairment, its pharmacokinetic profile may need to be closely monitored in patients with severe renal dysfunction due to the increased plasma exposure that occurs in such conditions. The evidence currently available stems predominantly from Japanese populations; thus, ongoing studies in more diverse populations (for instance, in the US via Phase Ib trials) are essential to confirm its efficacy and safety across broader demographics. 
Another consideration is the evolving landscape of off-target effects. While the drug is primarily used for gout and hyperuricemia, there remains uncertainty regarding the long-term benefits of urate-lowering therapy in preventing cardiovascular events or in slowing the progression of CKD beyond what is achieved with traditional medications. Further studies are needed to delineate the exact role of dotinurad in these potentially off-label indications. 
Finally, like all therapeutic agents, the potential for drug-drug interactions, though lower with dotinurad, is not entirely absent. In combination regimens—particularly when used alongside xanthine oxidase inhibitors or other medications for comorbid conditions—the clinician must remain vigilant and consult relevant pharmacokinetic studies to avoid unintended adverse interactions.

Conclusion 
In summary, dotinurad is a novel, chemically well-characterized small molecule with an excellent pharmacological profile. It functions through highly selective inhibition of URAT1, thereby lowering serum uric acid levels effectively and safely. Its primary approved indications cover the treatment of gout and hyperuricemia, conditions that result from the deposition of monosodium urate crystals in joints and other tissues. Clinical trials, conducted primarily in Japanese populations, have confirmed that dotinurad not only decreases serum uric acid levels in a dose-dependent manner but also achieves target uric acid levels in a high percentage of patients. This efficacy extends to long-term management with a once-daily dosing regimen, ensuring ease of use and adherence among patients. 

Furthermore, emerging evidence suggests that dotinurad may potentially be useful for other hyperuricemic conditions, including its off-label use in patients with chronic kidney disease and possibly even in the context of heart failure, given the interplay between hyperuricemia and these comorbidities. The favorable safety profile—marked by a lower incidence of liver-related adverse effects and minimal interference with other renal transporters—further enhances its attractiveness as a therapeutic option. Nonetheless, clinicians need to be mindful of the transient increases in urinary uric acid excretion during the early phase of treatment and should monitor patients accordingly, particularly those with pre-existing renal impairment. 

When compared with other medications in the same therapeutic area, dotinurad's advantages include its high selectivity against URAT1, efficacy comparable to established agents like febuxostat, and a manageable dosing schedule. However, limitations—such as the need for further data in diverse populations and the potential for transient urinary changes—highlight areas where continued post-marketing surveillance and additional studies are required. 

Overall, dotinurad represents a significant advancement in the management of gout and hyperuricemia. Its role in both primary and, potentially, off-label applications, combined with a robust safety and efficacy profile, positions it as an important therapeutic option in current and future treatment paradigms. The continued investigation into its additional benefits in conditions like CKD and heart failure may further expand its clinical utility. Given these multifaceted aspects, dotinurad is expected to contribute to improved patient outcomes and a more tailored approach in managing hyperuricemia and its associated disorders.

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