Comparative efficacy and safety of uricosuric agents in the treatment of gout or hyperuricemia: a systematic review and network meta-analysis.

OBJECTIVES: The current world witnesses a greatly increased prevalence and incidence of hyperuricemia and gout with unfortunately the comparative efficacy and safety of present available uricosuric agents remaining uncertain. We herein aimed to investigate the most appropriate uricosuric agent for gout or hyperuricemia patients. METHOD: PubMed, Embase, Cochrane Library databases, and ClinicalTrials.gov from inception to 2 July 2022 were searched to retrieve eligible studies assessing efficacy and safety of uricosuric drugs in hyperuricemia or gout patients. Network meta-analysis was carried out using the Stata 16.0 software. RESULTS: Twelve randomized controlled trials comprising 1851 patients were eventually included. Network meta-analysis showed that dotinurad 4 mg once daily, verinurad, dotinurad 2 mg once daily, dotinurad 1 mg once daily, and benzbromarone were the top 5 effective treatments to achieve target serum uric acid. Furthermore, dotinurad 4 mg once daily was more effective at achieving urate-lowering targets (RR of dotinurad 4 mg once daily vs. probenecid: 1.68, 95% CI [1.13; 2.50]) and safer (RR of probenecid vs. dotinurad 4 mg once daily: 1.77, 95% CI [0.69; 4.56]) than probenecid. CONCLUSIONS: This network meta-analysis demonstrated an important absolute benefit of dotinurad 4 mg once daily to achieve target serum uric acid and low risk of adverse events for drug treatment of gout or hyperuricemia patients. Additionally, verinurad might be used as an alternative uricosuric therapeutic option to dotinurad. These findings provided further comprehensive insight into the treatment value of current uricosuric agents for gout or hyperuricemia. Key Points 1. This is the first systematic review and network meta-analysis examining the efficacy and safety of currently available uricosuric agents in gout or hyperuricemia patients. 2. Recommended doses of dotinurad 4mg once daily used for the treatment of gout or hyperuricemia patients can significantly decrease serum uric acid levels. 3. The present findings will provide further comprehensive insight into the treatment value of certain uricosuric agents for gout or hyperuricemia.

Comparative efficacy and safety of dotinurad, febuxostat, and benzbromarone in hyperuricemic patients with or without gout: A network meta-analysis of randomized controlled trials.

OBJECTIVE: We aimed to assess the relative efficacy and safety of dotinurad (2 mg), benzbromarone (50 mg), and febuxostat (40 mg) in hyperuricemic patients with or without gout. MATERIALS AND METHODS: A Bayesian network meta-analysis was performed to combine direct and indirect evidence from randomized controlled trials (RCTs) to evaluate the efficacy and safety of dotinurad (2 mg), benzbromarone (50 mg), febuxostat (40 mg), and placebo in hyperuricemic patients with or without gout. RESULTS: Four RCTs, including 516 patients, fulfilled the inclusion criteria. The number of patients who achieved the target serum uric acid (sUA) level was significantly higher in the febuxostat 40-mg group than in the placebo group (OR 660.50, 95% credible interval (CrI) 75.47 - 19,584.80). The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that febuxostat 40 mg was more likely to achieve the best target sUA level (SUCRA = 0.849), followed by dotinurad 2 mg (SUCRA = 0.651), benzbromarone 50 mg (SUCRA = 0.501), and placebo (SUCRA < 0.001). The frequency of adverse drug reactions in the dotinurad 2-mg group, and in the benzbromarone 50-mg group tended to be lower than in the febuxostat 40-mg group. CONCLUSION: Febuxostat 40 mg and dotinurad 2 mg tended to be more effective than benzbromarone 50 mg, while dotinurad 2 mg and benzbromarone 50 mg tended to be safer than febuxostat 40 mg in hyperuricemic patients with or without gout.

Implementation Status of Liver Function Tests for Monitoring Benzbromarone-Induced Hepatotoxicity: An Epidemiological Survey Using the Japanese Claims Database.

A major adverse effect of benzbromarone is hepatotoxicity. Therefore, periodic liver function tests are required at least for the first 6 months of benzbromarone administration. However, it is not clear whether the relevant blood tests are implemented appropriately. Here, we performed a cross-sectional survey of the implementation status of liver function tests in patients who were newly prescribed benzbromarone, using the Japanese large claims database. Male patients who were newly prescribed benzbromarone from January 2010 to December 2016 were included. We targeted patients who continued benzbromarone during the observation period (up to 180 d from the start of administration). The primary endpoint was the proportion of patients in whom periodic liver function tests were implemented. A periodic liver function test was defined as one or more liver function tests performed during both 1-90 and 91-180 d of initial benzbromarone administration. We labeled the tests as a "periodic test" or "non-periodic test" based on whether periodic liver function tests were performed or not, respectively. Furthermore, factors influencing non-periodic test were analyzed. Periodic testing was implemented only in 28.7% of patients. Additionally, factors such as number of hospital beds ≤19 (compared to 100-199 beds) and duration of the first prescription of benzbromarone were associated with non-periodic testing. Our study revealed that periodic liver function tests are not performed sufficiently in Japan. Thus, clinicians prescribing benzbromarone should be educated about the test. Our blood-test-based approach should be applied to other drugs and countries in future research.

Comparative study of a novel selective urate reabsorption inhibitor "dotinurad" among patient groups with different stages of renal dysfunction.

BACKGROUND: Dotinurad is a selective urate reabsorption inhibitor (SURI), which selectively inhibits URAT1 to lower serum uric acid levels in patients with hyperuricemia. Herein, the effects of dotinurad were compared among patient groups with different stages of renal dysfunction. METHODS: Patient data from four clinical trials were pooled and divided into four groups according to the stage of renal dysfunction to compare the effects of dotinurad at different stages. The grouping (stages G1-G3b) was based on the estimated glomerular filtration rate (eGFR) of the patients. In addition, patient data from a long-term study (34 or 58 weeks) were evaluated in the same manner. RESULTS: In the pooled analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 64.7-100.0% at a dose of 2 or 4 mg. In the long-term analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 60.0-100.0% at a dose of 2 or 4 mg. Although the outcomes in stage G3b were worse due to higher baseline serum uric acid levels, satisfactory outcomes were observed in all stages. Even in stages G3a and G3b, when renal function declined, the eGFR remained constant throughout the dose period. CONCLUSION: The efficacy of dotinurad was confirmed in hyperuricemic patients with normal renal function (stage G1) and mild to moderate renal dysfunction (stage G2-G3b). Dotinurad was found to be effective in the treatment of hyperuricemia in patients with mild to moderate renal dysfunction.

Novel monocyclic amide-linked phenol derivatives without mitochondrial toxicity have potent uric acid-lowering activity.

Although benzbromarone (BBR) is a conventional, highly potent uricosuric drug, it is not a standard medicine because it causes rare but fatal fulminant hepatitis. We transformed the bis-aryl ketone structure of BBR to generate novel monocyclic amide-linked phenol derivatives that should possess uric acid excretion activity without adverse properties associated with BBR. The derivatives were synthesized and tested for uric acid uptake inhibition (UUI) in two assays using either urate transporter 1-expressing cells or primary human renal proximal tubule epithelial cells. We also evaluated their inhibitory activity against mitochondrial respiration as a critical mitochondrial toxicity parameter. Some derivatives with UUI activity had no mitochondrial toxicity, including compound 3f, which effectively lowered the plasma uric acid level in Cebus apella. Thus, 3f is a promising candidate for further development as a uricosuric agent.

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

CONTEXT: Combining a sodium-glucose cotransporter 2 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 of 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-h uUA excretion. RESULTS: Both regimens lowered mean peak uUA excretion (least squares mean changes from baseline: -12.9 mg/h [95% confidence interval (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 vs 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. CLINICAL TRIAL REGISTRATION NUMBER: NCT03316131.

Clinical efficacy and safety of benzbromarone in elderly hypertensive patients with hyperuricemia.

To analyze the efficacy and safety of benzbromarone in elderly hypertensive patients with hyperuricemia. Sixty-six elderly hypertensive patients with hyperuricemia admitted to Beijing Civil Aviation General Hospital from February 2017 to February 2018 were enrolled in the study. According to computer randomization method, they were divided into two groups: The control group and the treatment group and there were 33 cases in each group. The routine treatment was used in the control group. The conventional treatment combined with benzbromarone treatment was applied to the treatment group. The clinical efficacy, blood pressure, blood uric acid level, inflammatory factor level and adverse event rate were analyzed. Clinical efficacy of the treatment group was higher than that of the control group (P<0.05); blood pressure, blood uric acid level, and inflammatory factor level in the treatment group was better than that of the control group (P<0.05); the incidence of adverse events in the treatment group was lower than that of the control group (P<0.05). Elderly hypertensive patients with hyperuricemia treated with benzbromarone have a significant clinical effect, which has a positive effect on improving clinical symptoms and reducing the probability of adverse events and has a high clinical promotion value.

Pharmacological Evaluation of Dotinurad, a Selective Urate Reabsorption Inhibitor.

The effect of dotinurad [(3,5-dichloro-4-hydroxyphenyl)(1,1-dioxo-1,2-dihydro-3H-1λ 6-1,3-benzothiazol-3-yl)methanone] was compared with that of commercially available uricosuric agents-namely, benzbromarone, lesinurad, and probenecid. Its effect on urate secretion transporters was evaluated using probe substrates for respective transporters. Dotinurad, benzbromarone, lesinurad, and probenecid inhibited urate transporter 1 (URAT1) with IC50 values of 0.0372, 0.190, 30.0, and 165 µM, respectively. Dotinurad weakly inhibited ATP-binding cassette subfamily G member 2 (ABCG2), organic anion transporter 1 (OAT1), and OAT3, with IC50 values of 4.16, 4.08, and 1.32 µM, respectively, indicating higher selectivity for URAT1. The hypouricemic effects of dotinurad and benzbromarone were evaluated in Cebus monkeys. Dotinurad, at doses of 1-30 mg/kg, concomitantly decreased plasma urate levels and increased fractional excretion of urate (FEUA) in a dose-dependent manner. On the contrary, benzbromarone, at a dose of 30 mg/kg, showed a modest effect on plasma urate levels. The inhibitory effect of dotinurad on urate secretion transporters was evaluated in Sprague-Dawley rats, with sulfasalazine and adefovir as probe substrates of ABCG2 and OAT1, respectively. Drugs, including febuxostat as a reference ABCG2 inhibitor, were administered orally before sulfasalazine or adefovir administration. Dotinurad had no effect on urate secretion transporters in vivo, whereas benzbromarone, lesinurad, probenecid, and febuxostat increased the plasma concentrations of probe substrates. These results suggested dotinurad is characterized as a selective urate reabsorption inhibitor (SURI), which is defined as a potent URAT1 inhibitor with minimal effect on urate secretion transporters, including ABCG2 and OAT1/3, because of its high efficacy in decreasing plasma urate levels compared with that of other uricosuric agents. SIGNIFICANCE STATEMENT: Our study on the inhibitory effects on urate transport showed that dotinurad had higher selectivity for urate transporter 1 (URAT1) versus ATP-binding cassette subfamily G member 2 (ABCG2) and organic anion transporter (OAT) 1/3 compared to other uricosuric agents. In Cebus monkeys, dotinurad decreased plasma urate levels and increased fractional excretion of urate in a dose-dependent manner. To determine the inhibitory effect of dotinurad on urate secretion transporters, we studied the movement of substrates of ABCG2 and OAT1 in rats. Dotinurad had no effect on these transporters, whereas the other uricosuric agents increased the plasma concentrations of the substrates. These results suggested dotinurad as a potent and selective urate reabsorption inhibitor is characterized by increased efficacy with decreasing plasma urate levels.

Benzbromarone in the treatment of gout.

BACKGROUND: Benzbromarone is a uricosuric drug that has been used in the treatment of gout over the last 30 years. Due to its potent inhibition of the dominant apical (luminal) urate exchanger in the human proximal tubule URAT1, it reduces the urate reabsorption, diminishing serum urate levels and therefore preventing gout flares. Through several clinical trials, Benzbromarone has been proved effective and safe, inclusive in patients with chronic kidney disease and as combination therapy with allopurinol. Due to hepatotoxicity reports, it was withdrawn from the European market by the manufacturer, however many authors have questioned the product's withdrawal due to a lack of clinical evidence in order to support its hepatotoxicity. Benzbromarone is still available in several European countries, New Zealand, Brazil and several other countries. Despite the product's marketing over more than 20 years after the first hepatotoxicity reports, we have found only five reports in our literature search, and no prospective or retrospective study correlating hepatotoxicity with benzbromarone use. SHORT CONCLUSION: Benzbromarone is a safe and effective molecule for the treatment of gout. However, due to in vitro and in vivo data related to hepatotoxicity, it is prudent to prescribe it with some caution, especially for patients with an already known liver condition.

Venous thromboembolism in patients with gout and the impact of hospital admission, disease duration and urate-lowering therapy.

BACKGROUND: Systemic inflammatory diseases have been associated with increased risk of venous thromboembolism. We aimed to quantify the risk of venous thromboembolism in patients with gout, the most common inflammatory arthritis, and to assess how disease duration, hospital admission and urate-lowering therapy affect this risk. METHODS: We used data from the population-representative, England-based Clinical Practice Research Datalink linked to Hospital Episode Statistics, to identify incident gout cases between 1998 and 2017. We matched cases individually to 1 control without gout on age, gender, general practice and follow-up time. We calculated absolute and relative risks of venous thromboembolism, stratified by age, gender and hospital admission. Among those with gout, we assessed the risk of venous thromboembolism by exposure to urate-lowering therapy. RESULTS: We identified 62 234 patients with incident gout matched to 62 234 controls. Gout was associated with higher risk of venous thromboembolism compared with controls (absolute rate 37.3 [95% confidence interval (CI) 35.5-39.3] v. 27.0 [95% CI 25.5-28.9] per 10 000 person-years, adjusted hazard ratio [HR] 1.25, 95% CI 1.15-1.35). The excess risk in patients with gout, which was sustained up to a decade after diagnosis, was present during the time outside hospital stay (adjusted HR 1.30, 95% CI 1.18-1.42), but not during it (adjusted HR 1.01, 95% CI 0.83-1.24). The risk of venous thromboembolism was similar among patients prescribed versus not prescribed urate-lowering therapy (incidence rate ratio 1.04, 95% CI 0.89-1.23). INTERPRETATION: Gout was associated with higher risk of venous thromboembolism, particularly when the patient was not in hospital and regardless of exposure to urate-lowering therapy. Although the observed excess risk may not be sufficient to warrant preventive intervention, clinical vigilance may be required when caring for these patients.

Benzbromarone as a possible cause of acute kidney injury in patients with urolithiasis: Two case reports.

RATIONALE: Reports of acute kidney injury (AKI) associated with benzbromarone use in patients with hyperuricemia (HUA) are rare so far. PATIENT CONCERNS: We describe 2 unique clinical patterns in which benzbromarone was a possible cause of AKI following self-medication for HUA. In case 1, a 45-year-old man developed AKI after taking 100 mg of benzbromarone. His serum creatinine (Scr) increased to 2.3 mg/dL on day 2 after benzbromarone administration. Ultrasound showed multiple small stones in both kidneys, and the 24-hour urine uric acid level was 3128 mg. In case 2, a 17-year-old male student presented with AKI after self-administration of 50 mg of benzbromarone. His Scr increased to 6.8 mg/dL on day 3 after benzbromarone administration. Ultrasound showed multiple stones in the left kidney. DIAGNOSIS: Both patients underwent renal biopsy, with findings of acute tubular interstitial nephropathy in case 1 and acute tubular damage in case 2. Drug-induced AKI was considered. INTERVENTIONS: Both cases were treated supportively with intravenous hydration only. In both patients, the Scr level recovered within 0.5 months and renal function was normal 3 months after discharge. LESSONS: Oral benzbromarone is widely used in Asian counties to treat HUA and the adverse effects are mostly mild. However, clinicians should be alert for benzbromarone-induced AKI. Moreover, uricosuric drugs should only be used after exclusion of urolithiasis and other contraindications.

Safety and tolerability of available urate-lowering drugs: a critical review.

INTRODUCTION: Urate-lowering therapy (ULT) is the cornerstone of gout management, which is a widespread chronic illness characterized by hyperuricemia, arthropathy, tophus development, and urolithiasis. Since asymptomatic increased serum urate levels are associated with a higher risk of cardiovascular, renal and metabolic disorders, a larger use of ULTs in the general population is expected in the near future. AREAS COVERED: This review will focus on the safety and tolerability profile of the available urate-lowering drugs: xanthine oxidase inhibitors (XOIs), uricosuric agents and injectable uricases. EXPERT OPINION: Older drugs for ULT like allopurinol are well studied and extensively described from typical adverse effects (mild skin rash) to unusual fatal reactions, while febuxostat seems to be overall well tolerated. More evidence is required to define the safety profile of topiroxostat, arhalofenate, tranilast, and sulfinpyrazone. Furthermore, there are some unanswered questions about the pharmacological interactions of probenecid and the hepatotoxicity of benzbromarone. Despite a limited use in clinical practice, combination therapy with lesinurad or verinurad and XOI is not frequently accompanied by side effects. Rasburicase and pegloticase are usually well tolerated with some specific exceptions. Before prescribing UL drugs, physicians should take into account their safety profile tailoring the treatment on the patient characteristics.

Safety and efficacy of verinurad, a selective URAT1 inhibitor, for the treatment of patients with gout and/or asymptomatic hyperuricemia in the United States and Japan: Findings from two phase II trials.

Objective: Evaluate efficacy/safety of verinurad monotherapy in patients with gout (Japan/US) or asymptomatic hyperuricemia (Japan).Methods: Two randomized, placebo-controlled, phase II studies were conducted (NCT01927198/NCT02078219). Patients were randomized to once-daily doses of placebo or escalating doses of verinurad (study 1: 5-12.5 mg; study 2: 2.5-15 mg). Primary endpoint was percentage change from baseline in serum urate (sUA) at week 12 (study 1)/week 16 (study 2). Safety was also assessed.Results: Most patients in study 1 (n = 171) were white (74.9%); all patients were Japanese in study 2 (n = 204). Least squares means (±SE) estimate of percentage change in sUA levels from baseline in study 1 was 1.2 ± 2.9 for placebo, and -17.5 ± 2.8, -29.1 ± 2.8, -34.4 ± 2.9 for verinurad 5, 10, 12.5 mg, respectively. In study 2, results were -2.4 ± 2.5 and -31.7 ± 2.5, -51.7 ± 2.6,-55.8 ± 2.5, respectively. Difference from placebo was significant for each verinurad dose (p<.0001). The proportion of patients with treatment-emergent adverse events (TEAEs) was similar across all groups. Renal-related TEAEs were more common with verinurad than placebo.Conclusion: Verinurad monotherapy resulted in sustained reductions in sUA in Japanese/US patients but renal AEs occurred, so verinurad alone is not recommended for treatment of hyperuricemia or gout. The renal consequences of excessive uric acid excretion deserve study.

Efficacy and Safety of Lesinurad in Patients with Hyperuricemia Associated with Gout: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To evaluate the efficacy and safety of lesinurad for the treatment of hyperuricemia in patients with gout. DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). PATIENTS OR PARTICIPANTS: Five RCTs, which included 1959 patients, compared the efficacy and safety of lesinurad in patients with hyperuricemia associated with gout. MEASUREMENTS AND RESULTS: Relevant studies were identified from PubMed, EMBASE, Cochrane Library databases, and the ClinicalTrials.gov registry. Two reviewers independently assessed the studies. Individual effect sizes were standardized, and a meta-analysis was conducted to calculate the pooled effect size by using a random-effect model. The primary outcomes were the proportion of patients achieving target serum uric acid (sUA) levels by month 6 and the mean sUA levels at month 6 and month 12. Gout-related outcomes were also assessed. The secondary outcome was the number of treatment-emergent adverse events (TEAEs). Compared with xanthine oxidase inhibitor (XOI) monotherapy, lesinurad 200 mg or 400 mg in combination with allopurinol or febuxostat exhibited a higher proportion of patients achieving target sUA levels of < 6.0 mg/dl or < 5.0 mg/dl, respectively, by month 6. Lesinurad-plus-XOI groups also significantly sustained lower mean sUA levels at month 6 and month 12 compared to XOI alone group. In gout-related outcomes, no significant treatment group differences favored lesinurad. The number of TEAEs was comparable between the lesinurad 200 mg-plus-XOI group and the XOI-monotherapy group. Although lesinurad 400 mg monotherapy demonstrated superior efficacy compared with placebo, significantly more TEAEs occurred. CONCLUSIONS: Although the combination of lesinurad 200 mg and XOI is effective and well tolerated for treating patients with gout who have not achieved an adequate response to XOI monotherapy, clinical gout-related outcomes were not improved. Therefore, additional studies investigating the long-term clinical implication of lesinurad are warranted.

Risk of fragility fracture among patients with gout and the effect of urate-lowering therapy.

BACKGROUND: Previous studies that quantified the risk of fracture among patients with gout and assessed the potential effect of urate-lowering therapy have provided conflicting results. Our study aims to provide better estimates of risk by minimizing the effect of selection bias and confounding on the observed association. METHODS: We used data from the Clinical Practice Research Datalink, which records primary care consultations of patients from across the United Kingdom. We identified patients with incident gout from 1990 to 2004 and followed them up until 2015. Each patient with gout was individually matched to 4 controls on age, sex and general practice. We calculated absolute rate of fracture and hazard ratios (HRs) using Cox regression models. Among patients with gout, we assessed the impact of urate-lowering therapy on fracture, and used landmark analysis and propensity score matching to account for immortal time bias and confounding by indication. RESULTS: We identified 31 781 patients with incident gout matched to 122 961 controls. The absolute rate of fracture was similar in both cases and controls (absolute rate = 53 and 55 per 10 000 person-years, respectively) corresponding to an HR of 0.97 (95% confidence interval 0.92-1.02). Our finding remained unchanged when we stratified our analysis by age and sex. We did not observe statistically significant differences in the risk of fracture among those prescribed urate-lowering therapy within 1 and 3 years after gout diagnosis. INTERPRETATION: Overall, gout was not associated with an increased risk of fracture. Urate-lowering drugs prescribed early during the course of disease had neither adverse nor beneficial effect on the long-term risk of fracture.

Comparison of Clinical Advantage between Topiroxostat and Febuxostat in Hemodialysis Patients.

To determine the response of hemodialysis (HD) patients to topiroxostat after a switch from febuxostat, we evaluated the efficacy, tolerability, and serum concentration of topiroxostat in HD patients after the switch. In this 16-month prospective observational study, we assessed the serum uric acid (UA) levels, other laboratory data, and serum topiroxostat concentrations of 10 HD patients who had been receiving febuxostat at a dose of 10 mg/d for over 1 year. No statistical difference was observed between the tolerability index at baseline and 16 months after the switch to topiroxostat. Serum UA after the switch in all patients (attained serum UA levels of ≤6 mg/dL) was 5.6±1.7 mg/dL (60%) at baseline, 4.9±0.5 mg/dL (100%) at 6 months and 5.7±0.4 mg/dL (50%) at 16 months (p=0.25), respectively. In patients with baseline serum UA levels >6 mg/dL, serum UA was significantly reduced at 6 and 16 months compared with baseline. Minimum serum concentrations of serum topiroxostat were lower than the limit of quantification (<25 ng/mL). Our results indicate that a switch from febuxostat 10 mg/d to topiroxostat 40 mg/d might reduce serum UA levels, with no change in other clinical laboratory data over the long term. These effects were more frequent in patients with high serum UA levels. Furthermore, topiroxostat therapy was more cost effective than febuxostat therapy. Thus, topiroxostat therapy could be a better treatment option for HD patients who develop high serum UA levels after febuxostat 10 mg/d administration.

Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects.

PURPOSE: Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy adult males. SUBJECTS AND METHODS: This was a Phase I, randomized, double-blind, placebo-controlled, single and multiple ascending dose study. Panels of eight male subjects received a single oral dose of verinurad or placebo in either a fasted or fed state; panels of 10-12 male subjects received ascending doses of once-daily verinurad or placebo in a fasted state for 10 days. Serial blood and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs). RESULTS: A total of 81 adult males completed the study. Following single doses of verinurad, maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose-proportional manner; Cmax occurred at 0.5-0.75 hours and 1.25 hours in the fasted and fed states, respectively. Food decreased AUC by 23% and Cmax by 37%-53%. There was a modest accumulation of verinurad following multiple daily doses. Verinurad reduced serum urate levels by up to 62% (40 mg, single dose) and 61% (10 mg, multiple dose). The increase in urinary excretion of uric acid was greatest in the first 6 hours after dosing and was still evident ≥24 hours for verinurad doses ≥2 mg. Verinurad was well tolerated at all doses. No serious AEs, severe AEs, discontinuations due to AEs, or clinically significant laboratory or ECG abnormalities were reported. CONCLUSION: Single and multiple doses of verinurad were well tolerated, absorption was rapid, and exposure was dose proportional. Verinurad increased urinary uric acid elimination and resulted in sustained reductions in serum urate. These data support further clinical evaluation of once-daily verinurad as a treatment for gout.

Lesinurad: A Review in Hyperuricaemia of Gout.

Lesinurad (Zurampic®) is an oral selective inhibitor of the URAT1 and OAT4 uric acid (UA) transporters of the kidney, via which it inhibits UA reabsorption and thus increases renal UA excretion and lowers serum UA (sUA) levels. Lesinurad 200 mg once daily is indicated for use in combination with a xanthine oxidase inhibitor (XOI) to treat hyperuricaemia in adults with gout who have not achieved target sUA levels with an XOI alone. Approval was based on three 12-month phase 3 trials that evaluated lesinurad in combination with allopurinol in adults with gout inadequately responsive to allopurinol (CLEAR 1 and 2) and in combination with febuxostat in adults with tophaceous gout (CRYSTAL). The target sUA level of <6 mg/dL at 6 months (primary endpoint) was achieved by significantly more lesinurad plus allopurinol than placebo plus allopurinol recipients in the CLEAR trials. In CRYSTAL (which enrolled patients regardless of prior XOI experience, and included 3 weeks of febuxostat before randomization), the proportion of patients who achieved an sUA target of <5 mg/dL did not reach statistical significance between lesinurad plus febuxostat and placebo plus febuxostat at 6 months (primary endpoint), although significantly favoured the lesinurad plus febuxostat group at 12 months. Notably, the sUA target of <5 mg/dL at 6 months was met with lesinurad plus febuxostat in the CRYSTAL subgroup that had uncontrolled hyperuricaemia at baseline, despite having received febuxostat pre-randomization. Lesinurad plus XOI regimens were generally not associated with improvements in flares and tophi in these trials, although clinical benefit became more apparent in 12-month extension studies; the regimens were also generally well tolerated. Thus, lesinurad, in combination with an XOI, is an emerging option for the treatment of hyperuricaemia in adults with gout who have not achieved target sUA levels with an XOI alone.

Effect of Uric Acid Lowering on Renin-Angiotensin-System Activation and Ambulatory BP: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Higher serum uric acid levels, even within the reference range, are strongly associated with increased activity of the renin-angiotensin system (RAS) and risk of incident hypertension. However, the effect of lowering serum uric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adults with serum uric acid ≥5.0 mg/dl to uric acid lowering with either probenecid or allopurinol, or to placebo. The primary endpoints were kidney-specific and systemic RAS activity. Secondary endpoints included mean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping. RESULTS: Allopurinol and probenecid markedly lowered serum uric acid after 4 and 8 weeks compared with placebo (mean serum uric acid in allopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and 5.6 mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flow response to captopril (in ml/min per 1.73 m2) from baseline to 8 weeks, was -4 (-25 to 32) in the probenecid group (P=0.83), -4 (-16 to 9) in the allopurinol group (P=0.32), and 1 (-21 to 17) in the placebo group (P=0.96), with no significant treatment effect (P=0.77). Similarly, plasma renin activity and plasma angiotensin II levels did not significantly change with treatment. The change in mean (±SD) 24-hour systolic BPs from baseline to 8 weeks was -1.6±10.1 with probenecid (P=0.43), -0.4±6.1 with allopurinol (P=0.76), and 0.5±6.0 with placebo (P=0.65); there was no significant treatment effect (P=0.58). Adverse events occurred in 9%, 12%, and 2% of those given probenecid, allopurinol, or placebo, respectively. CONCLUSIONS: In contrast to animal experiments and observational studies, this randomized, placebo-controlled trial found that uric acid lowering had no effect on kidney-specific or systemic RAS activity after 8 weeks or on mean systolic BP. These data do not support the hypothesis that higher levels of uric acid are a reversible risk factor for increased BP.