Integrated safety studies of the urate reabsorption inhibitor lesinurad in treatment of gout

Terkeltaub, Robert; Goldfarb, David S.; Schechter, Bruce M; Valiyil, Ritu; Jalal, Diana; Pillinger, Michael H.; White, William Β.

doi:10.1093/rheumatology/key245

Cited by 19 publications

(13 citation statements)

References 23 publications

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“…Lesinurad is a selective uric acid reuptake inhibitor that acts through inhibition of the uric acid transporter 1 (URAT1) [ 126 ]. It has been approved for use at a dose of 200 mg in combination with an XOI such as Allopurinol or Febuxostat [ 127 ]. It is not approved for use as a monotherapy or at doses greater than 200 mg due to increases in treatment-emergent adverse events (TEAE) and cardiovascular events ( Table 3 ) [ [128] , [129] , [130] , [131] ].…”

Section: Potential Impact Of U-shaped Association Of Serum Uric Acid ...mentioning

confidence: 99%

U-shaped association of uric acid to overall-cause mortality and its impact on clinical management of hyperuricemia

et al. 2022

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Section: Potential Impact Of U-shaped Association Of Serum Uric Acid ...mentioning

confidence: 99%

U-shaped association of uric acid to overall-cause mortality and its impact on clinical management of hyperuricemia

et al. 2022

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“…Lesinurad, when combined with an XOI, is effective in lowering sUA levels in clinical trials ( 6-8 ). However, concerns have been raised when using URAT1 inhibitors as monotherapy regarding their impact on kidney function, owing to elevations in serum creatinine, partly attributed to increased urinary excretion rates of UA in tubules ( 14 ). Verinurad, a newer and more specific URAT1 inhibitor with an extended-release profile, is highly effective in lowering UA levels without adversely increasing peak urinary UA (uUA) excretion when combined with an XOI ( 15 ).…”

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confidence: 99%

Dapagliflozin Added to Verinurad Plus Febuxostat Further Reduces Serum Uric Acid in Hyperuricemia: The QUARTZ Study

Stack

Han

Goldwater

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Combining a sodium–glucose cotransporter 2 (SGLT2) inhibitor with a xanthine oxidase inhibitor (XOI) and a urate transporter 1 (URAT1) inhibitor may enhance serum uric acid (sUA) lowering. However, concerns exist regarding high urinary UA (uUA) excretion rates and subsequent crystallization in renal tubules. Objective To assess whether dapagliflozin added to verinurad, a selective URAT1 inhibitor, and febuxostat, an XOI, increases uUA excretion. Design Randomized, placebo-controlled, 2-way crossover study (NCT03316131). Patients Adults with asymptomatic hyperuricemia. Interventions Subjects (N = 36) were randomized to oral once-daily 9 mg verinurad plus 80 mg febuxostat plus 10 mg dapagliflozin for 7 days and 7 days’ oral once-daily 9 mg verinurad plus 80 mg febuxostat plus placebo with an intervening 7- to 21-day washout period. Main outcome measure Difference in peak uUA excretion between groups from baseline to Day 7. Secondary outcomes included changes in sUA levels and 24-hour uUA excretion. Results Both regimens lowered mean peak uUA excretion (least squares mean changes from baseline: –12.9 mg/h [95% CI: –21.0 to –4.7] [dapagliflozin]; –13.2 mg/h [95% CI –21.3 to –5.0] [placebo]). sUA concentrations were lower with dapagliflozin (mean treatment difference –62.3 µmol/L [95% CI –82.8 to –41.8]). Dapagliflozin did not impact verinurad pharmacokinetics, its main metabolites, or febuxostat; or fasting plasma glucose levels versus verinurad plus febuxostat. There were no clinically relevant changes in safety parameters. Conclusions Dapagliflozin further reduced sUA without influencing uUA excretion, suggesting that its combination with verinurad and febuxostat at the doses tested does not adversely affect kidney function.

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“…Finally, the side effects of lesinurad, which is an URAT-1 inhibitor that was recently made available in the market, has gained clinical attention. In terms of the side effects of such drug, the main concern is the increase in serum creatinine concentration [36]. Because hyperuricemia/gout is a chronic condition and its therapy must continue for an extended period, cautious observation of any potential side effects, including renal damage, is also crucial in future treatments with dotinurad.…”

Section: Dotinurad As a Future Therapeutic Option For Hyperuricemia/goutmentioning

confidence: 99%

Dotinurad: a novel selective urate reabsorption inhibitor as a future therapeutic option for hyperuricemia

Kuriyama

2019

Clin Exp Nephrol

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Gout is a chronic inflammatory disease caused by precipitation of urate crystals in the joints, kidneys, and urinary tract. Independent of urate deposition disorders, recent studies have shown a positive association between circulating uric acid (UA) levels and cardiovascular (CV) diseases. These results indicate that UA is a precipitating factor of both gout and the progression of CV diseases, including hypertension and/or chronic kidney disease (CKD). A large body of evidence has shown that UA-lowering therapies are effective in preventing the progression of hypertension/CKD and that a causal relationship exists between serum UA level and CV diseases. Despite the urgent need for effective UA-lowering drugs that can be used to obtain better therapeutic outcomes and prognosis, only few drugs have been developed in the past decades. Recently, febuxostat and topiroxostat, which are xanthine oxidoreductase inhibitors, were developed and used in clinical practice. Of note, after the approval of lesinurad, which is a urate transporter-1 (URAT-1) inhibitor, in the United States in 2015, dotinurad (Fig. 1), a novel promising drug with selective UA reabsorption inhibitory property, was recently developed in Japan in 2018. Dotinurad is indicated for patients with hyperuricemia/gout as most patients with hyperuricemia are classified into "underexcretion type", which requires the inhibition of URAT-1 to excrete excess UA via the kidney. Focusing on dotinurad, the present study highlighted the multifaceted preliminary new trials that assessed for drug efficacy and safety, pharmacokinetics (PK) according to age and gender, the presence or absence of liver and kidney disorders, drug interactions with NSAID, and non-inferiority of dotinurad to either febuxostat or benzbromarone. A series of studies included in this supplemental review indicate that dotinurad reduces serum UA levels, and its efficacy and safety are similar to those of other UA-lowering agents currently used even in hyperuricemic patients with various clinical conditions. Moreover, two exploratory studies with a small sample size were conducted to compare PK parameters between patients with overproduction-and underexcretion-type hyperuricemia, and results showed that the effects of UA-lowering agents were comparable between the two subtype groups.

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Integrated safety studies of the urate reabsorption inhibitor lesinurad in treatment of gout

Cited by 19 publications

References 23 publications

U-shaped association of uric acid to overall-cause mortality and its impact on clinical management of hyperuricemia

U-shaped association of uric acid to overall-cause mortality and its impact on clinical management of hyperuricemia

Dapagliflozin Added to Verinurad Plus Febuxostat Further Reduces Serum Uric Acid in Hyperuricemia: The QUARTZ Study

Dotinurad: a novel selective urate reabsorption inhibitor as a future therapeutic option for hyperuricemia

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