topiroxostat and Gout

We aimed to assess the relative efficacy and safety of topiroxostat at different dosages in hyperuricemic patients with or without gout.. A Bayesian network meta-analysis was performed to combine direct and indirect evidence from randomized controlled trials (RCTs) for evaluating the efficacy and safety of topiroxostat at different dosages, allopurinol 200 mg, and placebo in hyperuricemic patients with or without gout.. Five RCTs, including 733 patients, fulfilled the inclusion criteria. The number of patients who had achieved a target serum uric acid (sUA) level was significantly higher in the topiroxostat 200 mg group than in the placebo group (odds ratio, 1,023; 95% credible interval, 157.7 - 26,260). Similarly, the number of patients who had achieved the target sUA level was significantly higher with topiroxostat at other dosages and allopurinol than with placebo. The ranking probability based on the surface under the cumulative ranking curve indicated that topiroxostat 200 mg was more likely to achieve the best target sUA level, followed by topiroxostat 80 mg, allopurinol 200 mg, topiroxostat 120 mg, topiroxostat 160 mg, topiroxostat 60 mg, topiroxostat 40 mg, and placebo. The frequency of adverse events (AEs) in the placebo group was lower than that in the topiroxostat 40 mg, topiroxostat 60 mg, and topiroxostat 200 mg groups.. Topiroxostat 200 mg was the most effective treatment option for hyperuricemic patients with or without gout, with an increased risk of AEs.

Topics: Gout; Gout Suppressants; Humans; Network Meta-Analysis; Nitriles; Pyridines; Randomized Controlled Trials as Topic; Treatment Outcome; Uric Acid

Inhibitors of xanthine oxidoreductase decrease production of uric acid, thus they act as hypouricemic drugs. Allopurinol, a prototypical xanthine oxidoreductase inhibitor, has been widely prescribed for treatment of gout and hyperuricemia. However, severe side effects of allopurinol may occur in patients with renal insufficiency. Recently, novel nonpurine selective inhibitors of xanthine oxidoreductase have been developed as potential alternatives to allopurinol. They have different inhibition mechanisms, utilizing the enzyme structure and the reaction mechanism. Such variation of the inhibition mechanism affects/in vivo/hypouricemic effects of the inhibitors.

Topics: Allopurinol; Drug Design; Enzyme Inhibitors; Febuxostat; Gout; Gout Suppressants; Humans; Hyperuricemia; Nitriles; Pyrazoles; Pyridines; Thiazoles; Xanthine Dehydrogenase

Topiroxostat-a novel selective xanthine oxidoreductase inhibitor-has been reported to reduce serum urate levels. The purpose of this study was to assess the efficacy and safety of long-term topiroxostat administration in Japanese hyperuricemic patients with or without gout.. This multicenter, open-label study evaluated the efficacy and safety of long-term twice-daily oral topiroxostat administration in patients with or  without gout. The initial topiroxostat dosage was 40-80 mg/day, and the maintenance dosage was 120 mg/day, which was increased to 240 mg/day at 40 mg increments if the serum urate level exceeded 6.0 mg/dL.. Serum urate level, which was the primary endpoint, decreased stably over time and showed significant reduction on the final visit (38.44% ± 13.34%) compared with that at the baseline. Both urinary albumin/creatinine ratio and mean blood pressure significantly improved. The overall incidence rate of adverse drug reactions to topiroxostat was 67.8%; on the final visit, the rate of adverse drug reactions was 66.7% with 120 mg/day, 72.2% with 160 mg/day, 53.8% with ≥ 200 mg/day, and 100% with the other dosages. On the final visit, the incidence of gouty arthritis, for which a causal relationship with topiroxostat could not be ruled out, was 4.1% overall, 4.8% with 120 mg/day, 0% with 160 mg/day, and 7.7% with ≥ 200 mg/day.. We verified the efficacy and safety of 58-week oral topiroxostat administration at stepwise increments to up to 240 mg/day.. JAPIC CTI-101068.

Topics: Administration, Oral; Adult; Aged; Drug Administration Schedule; Enzyme Inhibitors; Female; Gout; Gout Suppressants; Humans; Hyperuricemia; Japan; Male; Middle Aged; Nitriles; Pyridines; Treatment Outcome; Uric Acid

Topiroxostat, a selective xanthine oxidoreductase inhibitor, is used in Japan for the treatment of hyperuricemic patients with or without gout. In terms of the effectiveness of topiroxostat in lowering serum urate levels, the dose-response relationship has been evaluated; however, it remains to be verified. A randomized, multi-center, double-blinded study of topiroxostat was performed for Japanese hyperuricemic patients with or without gout. During the 16-week study, 157 Japanese hyperuricemic patients with or without gout were randomly assigned to receive a placebo, topiroxostat at 120 or 160 mg/day, or allopurinol at 200 mg/day. The primary endpoint of this study was to determine the lowering rate of serum uric acid levels compared to those of baseline at the end of administration. A dose-response relationship (regarding decreases in the serum urate levels) was confirmed for the placebo and topiroxostat at 120 and at 160 mg/day. Moreover, at the end of administration, the lowering rate of serum urate levels was determined to be -44.8% in the topiroxostat 160-mg/day group. No significant difference in the incidence of adverse events was observed among all groups, including the allopurinol group. The serum urate-lowering effect of topiroxostat was found to have a dose-response relationship in Japanese hyperuricemic patients with or without gout.

Topics: Adult; Allopurinol; Double-Blind Method; Female; Gout; Gout Suppressants; Humans; Hyperuricemia; Japan; Male; Middle Aged; Nitriles; Pyridines; Treatment Outcome; Uric Acid; Young Adult

In Japan, although topiroxostat, a selective xanthine oxidoreductase inhibitor, has been used for the treatment of patients with hyperuricemia including gout, no published randomized controlled studies evaluating the dose-dependent relationship with respect to the serum urate-lowering efficacy have been reported. The aim of this study was to evaluate the dose-dependent relationship with serum urate-lowering efficacy and safety of topiroxostat in Japanese hyperuricemic patients including gout.. We conducted an exploratory, phase 2a, multicentre, randomized, double-blind, 8-week, placebo-controlled study in Japanese hyperuricemic patients with or without gout. The study arms were placebo and topiroxostat 40, 60, 80 or 120 mg/day. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit.. One hundred and eighty-seven eligible patients were randomized and 186 received at least one dose of the study drug. The study results demonstrated a dose-dependent serum urate reduction effect ranging from 40 to 120 mg/day (P < 0·001, Jonckheere-Terpstra test). The mean per cent change in serum urate level from baseline at the final visit was -30·8% in the 120-mg group and 1·6% with placebo, with a between-group difference of -32·4% ([95% confidence interval, -38·9% to -25·9%]; P < 0·001). Incidences of overall adverse events (AEs) in the topiroxostat groups were comparable to those in the placebo group; however, the incidence of AEs in the 120-mg group was statistically lower than that in the placebo group. The incidences of gouty arthritis were not statistically but numerically higher in the topiroxostat 80- and 120-mg groups.. A dose-dependent serum urate-lowering efficacy of topiroxostat was observed in Japanese hyperuricemic male patients with or without gout. Further clinical studies aimed at evaluating the long-term safety and clinical efficacy are warranted.

Topics: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Follow-Up Studies; Gout; Gout Suppressants; Humans; Hyperuricemia; Japan; Male; Middle Aged; Nitriles; Pyridines; Treatment Outcome; Uric Acid; Xanthine Oxidase

There are no clinical reports that have compared topiroxostat, a selective xanthine oxidase inhibitor, with allopurinol in serum urate-lowering efficacy. The aim of this study was to compare the efficacy and safety of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout.. A phase 3, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study conducted in Japan. Patients who had inadequate serum urate levels (a gout patient: serum urate level ≥416·4 μmol/L; an asymptomatic hyperuricemic patient with specific complications (urinary lithiasis, hypertension, hyperlipidemia and/or diabetes): serum urate level ≥475·8 μmol/L; and an asymptomatic hyperuricemic patient with no specific complications: serum urate level ≥535·3 μmol/L) were randomized to topiroxostat 120 mg/day or allopurinol 200 mg/day, with an equal allocation ratio, for 16 weeks. To prevent the onset of gouty arthritis by rapid serum urate reduction, these doses were increased in a stepwise manner. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit.. Overall, 206 patients were randomly assigned to topiroxostat and allopurinol. Two hundred and three patients (allopurinol: n = 105, topiroxostat: n = 98) received at least one dose of the study drug and had their serum urate level assessed at least once. The baseline characteristics were comparable between groups. The mean age of patients was 53·0 ± 11·4 years and 99% of patients were male. The primary efficacy endpoint was -34·3 ± 11·1% in the allopurinol group (n = 105) and -36·3 ± 12·7% in the topiroxostat group (n = 98). Non-inferiority of the serum urate-lowering efficacy of topiroxostat to allopurinol was proved by the predefined non-inferiority margin (95% confidence interval, -5·3 to 1·3%). The overall incidences of adverse events and adverse drug reactions were similar between both groups.. Topiroxostat 120 mg/day provides non-inferior serum urate reduction compared with allopurinol 200 mg/day and is well tolerated in Japanese hyperuricemic patients with or without gout.

Topics: Adult; Aged; Allopurinol; Double-Blind Method; Female; Follow-Up Studies; Gout; Gout Suppressants; Humans; Hyperuricemia; Japan; Male; Middle Aged; Nitriles; Pyridines; Treatment Outcome; Uric Acid; Xanthine Oxidase

Topiroxostat, a selective xanthine oxidase inhibitor, shows effective reduction in the serum urate level in hyperuricemic patients with or without gout. The objective of this study was to evaluate the efficacy and safety of topiroxostat in hyperuricemic stage 3 chronic kidney disease patients with or without gout.. The study design was a 22-week, randomized, multicenter, double-blind study. The enrolled patients were randomly assigned to treatment with topiroxostat 160 mg/day (n = 62) or to the placebo (n = 61). The endpoints were the percent change in the serum urate level, change in the estimated glomerular filtration rate, the urinary albumin-to-creatinine ratio, the proportion of patients with serum urate levels of 356.88 μmol/L or less, blood pressure, and serum adiponectin.. After 22 weeks, although the changes in the estimated glomerular filtration rate and blood pressure were not significant, the percent change in the serum urate level (-45.38 vs. -0.08 %, P < 0.0001) and the percent change in urinary albumin-to-creatinine ratio (-33.0 vs. -6.0 %, P = 0.0092) were found to have decreased in the topiroxostat as compared with the placebo. Although the incidence of 'alanine aminotransferase increased' was higher in the topiroxostat, serious adverse event rates were similar in the two groups.. Topiroxostat 160 mg effectively reduced the serum urate level in the hyperuricemic stage 3 chronic kidney disease patients with or without gout.

Topics: Adiponectin; Aged; Albuminuria; Blood Pressure; Comorbidity; Creatinine; Double-Blind Method; Enzyme Inhibitors; Female; Glomerular Filtration Rate; Gout; Humans; Hyperuricemia; Male; Middle Aged; Nitriles; Prevalence; Pyridines; Renal Insufficiency, Chronic; Treatment Outcome; Uric Acid; Xanthine Oxidase

In the present study, we aimed to investigate the association between urate-lowering drugs and cardiovascular events, primarily focusing on the risk of febuxostat and topiroxostat when compared with allopurinol in Japan. We conducted an observational study with a cohort design using the National Database of Health Insurance Claims and Specific Health Checkups of Japan, including new urate-lowering drugs users between August 1, 2010, and March 31, 2018. Exposure and control groups were defined based on the first prescription of urate-lowering drugs as follows: febuxostat or topiroxostat for exposure groups, allopurinol for the control group, and benzbromarone for the secondary control group. The primary outcome was cardiovascular events, defined as a composite of acute coronary syndrome, cerebral infarction, and cerebral hemorrhage. Hazard ratios were estimated using a Cox proportional hazards model. The number of patients in each exposure and control group was 1,357,671 in the febuxostat group, 83,683 in the topiroxostat group, 1,273,211 in the allopurinol group, and 258,786 in the benzbromarone group. The adjusted hazard ratios for the cardiovascular risk were 0.97 (95% confidence interval [CI]: 0.95-0.98) for febuxostat and 0.84 (95% CI: 0.78-0.90) for topiroxostat groups. The benzbromarone group exhibited similar results. No increased cardiovascular risk was observed with febuxostat or topiroxostat when compared with allopurinol in patients with hyperuricemia in Japan. These results provide real-world evidence regarding the cardiovascular risk associated with urate-lowering drugs, indicating that no additional safety-related regulatory actions are warranted in Japan.

Topics: Allopurinol; Benzbromarone; Cardiovascular Diseases; Febuxostat; Gout; Gout Suppressants; Heart Disease Risk Factors; Humans; Insurance, Health; Japan; Risk Factors; Treatment Outcome; Uric Acid

Topics: Animals; Enzyme Inhibitors; Febuxostat; Gout; Hyperuricemia; Mice; Triazoles; Xanthine Dehydrogenase; Xanthine Oxidase

Topics: Benzbromarone; Bone Resorption; Enzyme Inhibitors; Gout; Humans; Male; Metatarsal Bones; Metatarsophalangeal Joint; Middle Aged; Nitriles; Osteogenesis; Osteophyte; Pyridines; Treatment Outcome; Uric Acid; Uricosuric Agents; Xanthine Oxidase

Various optimal medical therapies have been established to treat heart failure (HF) with reduced ejection fraction (HFrEF). Both HFrEF and HF with preserved ejection fraction (HFpEF) are associated with poor outcomes. We investigated the effect of topiroxostat, an oral xanthine oxidoreductase inhibitor, for HFpEF patients with hyperuricemia or gout.. In this nonrandomized, open-label, single-arm trial, we administered topiroxostat 40-160 mg/day to HFpEF patients with hyperuricemia or gout to achieve a target uric acid level of 6.0 mg/dL. The primary outcome was rate of change in log-transformed brain natriuretic peptide (BNP) level from baseline to 24 weeks after topiroxostat treatment. The secondary outcomes included amount of change in BNP level, uric acid evaluation values, and oxidative stress marker levels after 24 weeks of topiroxostat treatment. Thirty-six patients were enrolled; three were excluded before study initiation.. Change in log-transformed BNP level was -3.4 ± 8.9% (p = 0.043) after 24 weeks of topiroxostat treatment. The rate of change for the decrease in BNP level was -18.0 (-57.7, 4.0 pg/mL; p = 0.041). Levels of uric acid and 8-hydroxy-2'-deoxyguanosine/creatinine, an oxidative stress marker, also significantly decreased (-2.8 ± 1.6 mg/dL, p < 0.001, and -2.3 ± 3.7 ng/mgCr, p = 0.009, respectively).. BNP level was significantly lower in HFpEF patients with hyperuricemia or gout after topiroxostat administration; however, the rate of decrease was low. Further trials are needed to confirm our findings.

Topics: Aged; Aged, 80 and over; Biomarkers; Gout; Heart Failure; Humans; Hyperuricemia; Middle Aged; Natriuretic Peptide, Brain; Nitriles; Pilot Projects; Pyridines; Stroke Volume; Treatment Outcome; Uric Acid

Topiroxostat, a selective xanthine oxidoreductase inhibitor, is used for the management of hyperuricemic patients with or without gout in Japan. Accumulating evidence has demonstrated the efficacy of topiroxostat for the treatment of hyperuricemia with or without gout. However, the safety and efficacy of topiroxostat in the clinical setting remain unclear, and there is little large-scale clinical evidence. We conducted a post-marketing observational study over 54 weeks.. Patients were centrally enrolled, and case report forms of 4491 patients were collected between April 2014 and March 2019 from 825 medical sites.. Overall, 4329 patients were assessed for safety and 4253 patients for effectiveness. The overall incidence of adverse drug reactions was 6.95%, and the incidence rates of adverse drug reactions of gouty arthritis, hepatic dysfunction, and skin disorders, which are of special interest in this study, were 0.79%, 1.73%, and 0.95%, respectively. No case of serious gouty arthritis was observed. Serum urate levels decreased stably over time and showed a significant reduction rate at 54 weeks (21.19% ± 22.07%) and on the final visit (19.91% ± 23.35%) compared to the baseline. The rates for subjects who achieved serum uric acid levels ≤ 6.0 mg/dL at 18 and 54 weeks after administration were 43.80% and 48.28%, respectively.. This study suggests that there is no particular concern about adverse drug reactions or the efficacy of topiroxostat for hyperuricemic patients with or without gout in a post-marketing setting in Japan.

Topics: Adult; Enzyme Inhibitors; Female; Gout; Gout Suppressants; Humans; Hyperuricemia; Incidence; Japan; Male; Middle Aged; Nitriles; Product Surveillance, Postmarketing; Pyridines; Treatment Outcome; Uric Acid; Xanthine Dehydrogenase

Topics: Diabetic Nephropathies; Gout; Humans; Hyperuricemia; Nitriles; Pyridines

Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder caused by mutations in UMOD that encodes uromodulin. Topiroxostat, a novel non-purine analog, selectively inhibits xanthine oxidase and reduces the serum uric acid levels and the urinary albuminuria.. Genomic DNA of a patient was extracted from peripheral white blood. Exons and flanking sequences of UMOD were amplified by PCR with primers. Mutation analysis was performed by direct sequencing of the PCR products. The wild-type and mutant uromodulin were expressed in HEK293 cells and analyzed by western blotting, immunoprecipitation, immunofluorescence, and flow cytometry.. We identified an FJHN patient who carried a novel UMOD mutation G335A (C112Y). The levels of both cytosolic and secreted C112Y protein were significantly decreased compared with the wild-type, whereas the level of ubiquitination was higher in C112Y than that in the wild type. The half-life of C112Y was shortened and it was restored by a proteasome inhibitor MG132. Immunofluorescence revealed decreased levels of C112Y in the Golgi apparatus and on the plasma membrane. Expression of C112Y induced cellular apoptosis as revealed by flow cytometry. Apoptosis induced by C112Y was suppressed by topiroxostat.. C112Y causes its protein instability resulting cellular apoptosis which could be suppressed with topiroxostat.

Topics: Adult; Apoptosis; Gout; HEK293 Cells; Humans; Hyperuricemia; Kidney Diseases; Male; Mutation; Nitriles; Proteasome Endopeptidase Complex; Pyridines; Uromodulin