Comparison of pharmacokinetics and uric acid lowering effect between two different strength febuxostat formulations (80 mg vs. 40 mg) in healthy subjects
- International journal of clinical pharmacology and therapeutics
- Published almost 6 years ago
Febuxostat is a selective inhibitor of xanthine oxidase, which is used to manage hyperuricemia in patients with gout. The objective of the study was to compare the pharmacokinetics of two different strength of febuxostat formulations (80 mg and 40 mg).
Our goal was to establish a model for the evaluation of the effects of uricosuric agents and to clarify the underlying mechanism(s). The effects of a uricosuric agent co-treated with pyrazinamide, an anti-tubercular agent, on urate handling were examined in rats. Furthermore, the effects of uricosuric agents on urate uptake were evaluated using the vesicles of rat renal brush-border membrane. Treatment with probenecid, at a dose of 100 mg/kg, significantly increased the urinary urate to creatinine ratio (UUA/UCRE) in pyrazinamide-treated rats although the same treatment did not produce any uricosuric effects in intact rats. In this model, the urinary excretion of pyrazinecarboxylic acid (PZA), an active metabolite of pyrazinamide, was decreased by probenecid and indicated an inverse correlation between urinary excretion of urate and PZA. Furthermore, in the examination using FYU-981, a potent uricosuric agent, a more than 10-fold leftward shift of the dose-response relationship of the uricosuric effect was observed in pyrazinamide-treated rats when compared with intact rats. In the in vitro study, the treatment of the vesicles of rat renal brush-border membrane with PZA produced an increased urate uptake, which was inhibited by uricosuric agents. The pyrazinamide-treated model used in the present study seems to be valuable for the evaluation of uricosurics because of its higher sensitivity to these drugs when compared to intact rats, and this is probably due to the enhanced urate reabsorption accompanied with trans-stimulated PZA transport at the renal brush-border membrane.
Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in development for treatment of gout and asymptomatic hyperuricemia. This phase 1, single-blind, multiple-dose, drug-drug interaction study evaluated the pharmacokinetics (PK), pharmacodynamics, and safety/tolerability of verinurad in combination with febuxostat in healthy male volunteers. Twenty-three subjects were randomized and received once-daily doses of verinurad (or placebo) or febuxostat alone (days 1-7 and days 15-21), or verinurad + febuxostat on days 8-14. For combinations, subjects received verinurad 10 mg + febuxostat 40 mg or verinurad 2.5 mg + febuxostat 80 mg. Plasma/serum and urine samples were analyzed for verinurad, febuxostat, and uric acid. Safety was assessed by adverse events and laboratory tests. Febuxostat 40 mg had no effect on plasma exposure of verinurad 10 mg, whereas febuxostat 80 mg increased the maximum observed plasma concentration and the area under the plasma concentration-time curve of verinurad 2.5 mg by 25% and 33%, respectively. Verinurad had no effect on febuxostat PK. Maximal reduction in serum urate was 76% with verinurad 10 mg + febuxostat 40 mg versus verinurad 10 mg (56%) or febuxostat 40 mg (49%) alone and was 67% with verinurad 2.5 mg + febuxostat 80 mg versus verinurad 2.5 mg (38%) or febuxostat 80 mg (57%) alone. Verinurad increased, whereas febuxostat decreased, 24-hour fractional excretion and renal clearance of uric acid. There was no clinically significant drug-drug interaction between verinurad and febuxostat PK. The combination resulted in greater reductions of serum urate than either drug alone and was well tolerated at the studied doses.
The central strategy for effective gout management is longterm urate-lowering therapy to maintain the serum urate at a level below 0.36 mmol/l. We sought to determine the prevalence of gout and the quality of care in a national Australian general practice population.
Consumption of high fructose corn syrup (HFCS)-sweetened beverages increases serum urate and risk of incident gout. Genetic variants in SLC2A9, that exchanges uric acid for glucose and fructose, associate with gout. We tested association between sugar (sucrose)-sweetened beverage (SSB) consumption and prevalent gout. We also tested the hypothesis that SLC2A9 genotype and SSB consumption interact to determine gout risk.
A marked increase in gout was observed in England during the 17th to 20th centuries. Many have ascribed this rapid increase in gout to the introduction of wines that were laced with lead. In this article, we suggest another likely contributor, which is the marked increase in sugar intake that occurred in England during this period. Sugar contains fructose, which raises uric acid and increases the risk for gout. Sugar intake increased markedly during this period due to its introduction in liquors, tea, coffee and desserts. We suggest that the introduction of sugar explains why gout was originally a disease of the wealthy and educated, but gradually became common throughout society.
Independent and conjoint associations of gout and hyperuricaemia with total and cardiovascular mortality
- QJM : monthly journal of the Association of Physicians
- Published about 8 years ago
BACKGROUND: Gout and serum uric acid are associated with mortality but their simultaneous contributions have not been fully evaluated in the general population.Purpose: To explore the independent and conjoint relationships of gout and uric acid with mortality in the US population. METHODS: Mortality risks of gout and serum uric acid were determined for 15 773 participants, aged 20 years or older, in the Third National Health and Nutrition Examination Survey by linking baseline information collected during 1988-1994 with mortality data up to 2006. Multivariable Cox proportional hazards regression determined adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for each exposure and all analyses were conducted in 2011 and 2012. RESULTS: Compared with subjects without a history of gout, the multivariable HR for subjects with gout were 1.42 (CI 1.12-1.82) for total and 1.58 (CI 1.13-2.19) for cardiovascular mortality. Adjusted HRs per 59.5 µmol/l (1 mg/dl) increase in uric acid were 1.16 (CI 1.10-1.22) for total and cardiovascular mortality and this pattern was consistent across disease categories. In the conjoint analysis, the adjusted HRs for mortality in the highest two uric acid quartiles were 1.64 (CI 1.08-2.51) and 1.77 (CI 1.23-2.55), respectively, for subjects with gout, and were 1.09 (CI 0.87-1.37) and 1.37 (CI (1.11-1.70), respectively, for subjects without gout, compared with those without gout in the lowest quartile. A similar pattern emerged for cardiovascular mortality. CONCLUSION: Gout and serum uric acid independently associate with total and cardiovascular mortality. These risks increase with rising uric acid concentrations.
Gout is a crystal-deposition disease that results from chronic elevation of uric acid levels above the saturation point for monosodium urate (MSU) crystal formation. Initial presentation is mainly severely painful episodes of peripheral joint synovitis (acute self-limiting ‘attacks’) but joint damage and deformity, chronic usage-related pain and subcutaneous tophus deposition can eventually develop. The global burden of gout is substantial and seems to be increasing in many parts of the world over the past 50 years. However, methodological differences impair the comparison of gout epidemiology between countries. In this comprehensive Review, data from epidemiological studies from diverse regions of the world are synthesized to depict the geographic variation in gout prevalence and incidence. Key advances in the understanding of factors associated with increased risk of gout are also summarized. The collected data indicate that the distribution of gout is uneven across the globe, with prevalence being highest in Pacific countries. Developed countries tend to have a higher burden of gout than developing countries, and seem to have increasing prevalence and incidence of the disease. Some ethnic groups are particularly susceptible to gout, supporting the importance of genetic predisposition. Socioeconomic and dietary factors, as well as comorbidities and medications that can influence uric acid levels and/or facilitate MSU crystal formation, are also important in determining the risk of developing clinically evident gout.
From ancient times, gout has been related with excessive eating and drinking; however, it has not been until the last decade that a broader knowledge on dietary factors associated with hyperuricemia and gout has been achieved. Obesity, excessive intake of red meats and alcoholic beverages were already recognized as causal factors from Antiquity. Legumes and purine rich vegetables have been exculpated after the studies. New risk factors, not previously recognized, have been described such as fructose and sweetened beverages. Finally, protective factors have also been described, such as skimmed dairy products. Gout is characterized not only by an increase in uric acid, eventual episodes of arthritis, and chronic joint damage, but also by association with several comorbidities and increased cardiovascular risk. The adoption of more healthier dietary habits may contribute to better management of uricemia and also to a reduction of associated disea ses. The most common practice recommendations according to current knowledge and the main treatment guidelines are reviewed. Additional studies are needed on the actual efficacy in clinical practice of the adoption of specific dietary measures on the management and clinical course of patients with hyperuricemia and gout.
The renal tubule is a major route of clearance of uric acid, a product of purine metabolism. The links between reduced glomerular filtration rate (GFR), hyperuricemia, and gout in the general population are not well understood. The objective of the present study was to estimate prevalence of gout and hyperuricemia among people with impaired GFR in the US general population.