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 pharma...

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

Gout is well known as an inflammatory rheumatic disease presenting with arthritis and abnormal metabolism of uric acid. The recognition of diet-induced systemic metabolic pathways have provided new mechanistic insights and potential interventions on gout progression. However, the dietary recommendations for gouty patients generally focus on food categories, with few simultaneous considerations of nutritional factors and systemic metabolism. It is worthwhile to comprehensively review the mechanistic findings and potential interventions of diet-related nutrients against the development of gout, including purine metabolism, urate deposition, and gouty inflammation. Although piecemeal modifications of various nutrients often provide incomplete dietary recommendations, understanding the role of nutritional factors in gouty development can help patients choose their healthy diet based on personal preference and disease course. The combination of dietary management and medication may potentially achieve enhanced treatment effects, especially for severe patients. Therefore, the role of dietary and nutritional factors in the development of gout is systematically reviewed to propose dietary modification strategies for gout management by: (1) reducing nutritional risk factors against metabolic syndrome; (2) supplementing with beneficial nutrients to affect uric acid metabolism and gouty inflammation; and (3) considering nutritional modification combined with medication supplementation to decrease the frequency of gout flares.

/pdf/gout-and-diet-a-comprehensive-review-of-mechanisms-and-1py1fcxz.pdf

Gout and Diet: A Comprehensive Review of Mechanisms and Management

Disorders of uric acid metabolism may be associated with pathological processes in many diseases, including diabetes mellitus, cardiovascular disease, and kidney disease. These diseases can further promote uric acid accumulation in the body, leading to a vicious cycle. Preliminary studies have proven many mechanisms such as oxidative stress, lipid metabolism disorders, and rennin angiotensin axis involving in the progression of hyperuricaemia-related diseases. However, there is still lack of effective clinical treatment for hyperuricaemia. According to previous research results, NPT1, NPT4, OAT1, OAT2, OAT3, OAT4, URAT1, GLUT9, ABCG2, PDZK1, these urate transports are closely related to serum uric acid level. Targeting at urate transporters and urate-lowering drugs can enhance our understanding of hyperuricaemia and hyperuricaemia-related diseases. This review may put forward essential references or cross references to be contributed to further elucidate traditional and novel urate-lowering drugs benefits as well as provides theoretical support for the scientific research on hyperuricemia and related diseases.

/pdf/function-of-uric-acid-transporters-and-their-inhibitors-in-arfe1yd2s7.pdf

Function of Uric Acid Transporters and Their Inhibitors in Hyperuricaemia.

Objective Verinurad (RDEA3170) is a high-affinity, selective URAT1 inhibitor in development for treating gout and asymptomatic hyperuricaemia. This study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad in combination with febuxostat in adults with gout. Methods The phase IIa, open-label, multicentre study randomised 64 subjects into one of five cohorts to receive febuxostat (40 or 80 mg) alone or in combination with verinurad 2.5–20 mg. Serial plasma/serum and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse events, chemistry panels, ECGs and physical examinations. Results Serum pharmacodynamic data demonstrated the maximum percent decrease in serum urate (sUA) from baseline (E max ) at 8–12 hours after dosing. Verinurad with febuxostat decreased sUA in a dose-dependent manner. E max for verinurad with febuxostat 40 mg ranged from 52% to 77% vs 42% for febuxostat 40 mg alone; E max for verinurad with febuxostat 80 mg was 62%–82% vs 55% for febuxostat 80 mg alone. Urinary uric acid excretion rate was reduced below baseline by febuxostat alone and was comparable to baseline for verinurad with febuxostat. Verinurad plasma exposure increased with dose and was comparable when combined with febuxostat. No drug-drug interactions were observed. Verinurad was well tolerated with no clinically meaningful changes in laboratory values. Conclusion Verinurad administered with febuxostat produced dose-dependent decreases in sUA while maintaining urinary uric acid levels comparable to baseline. These dose combinations of verinurad and febuxostat were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. Trial registration number NCT02246673

https://rmdopen.bmj.com/content/rmdopen/4/1/e000584.full.pdf

Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study.

Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [14C]-uric acid in URAT1-expressing HEK293 cells with an IC50 value of 2.08 ± 0.31 μM, which was similar to that of RDEA3170 (its IC50 value was 1.47 ± 0.23 μM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC50 value of 91.55 ± 15.28 μM, whereas RDEA3170 at 100 μM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg−1 · d−1) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg−1 · d−1) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 μM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.

CDER167, a dual inhibitor of URAT1 and GLUT9, is a novel and potent uricosuric candidate for the treatment of hyperuricemia.

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.

https://accp1.onlinelibrary.wiley.com/doi/pdf/10.1002/cpdd.463

Pharmacokinetics, Pharmacodynamics, and Tolerability of Concomitant Administration of Verinurad and Febuxostat in Healthy Male Volunteers.

Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for treatment of hyperuricemia and gout. This phase 1b, multiple-dose, drug-drug interaction study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in combination with allopurinol. Adult males with gout were randomized to receive once-daily oral doses of allopurinol 300 mg or verinurad 10 mg alone for 7 days, allopurinol 300 mg + verinurad 10 mg on days 8 to 14, and the alternative single agent on days 15 to 21. Colchicine 0.6 mg was taken prophylactically for gout flares. Plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol (allopurinol active metabolite), colchicine (plasma only), and uric acid. Safety was assessed by adverse events (AEs) and laboratory tests. Verinurad plasma exposure was unaffected by allopurinol. Verinurad increased the maximum observed plasma concentration (Cmax ) for allopurinol by 33%; the area under the plasma concentration-time curve (AUC) was unaffected. Oxypurinol Cmax and AUC were reduced 32% and 38%, respectively, by verinurad. Colchicine plasma exposure was unaltered by verinurad. The maximum decrease in serum urate was greater with verinurad + allopurinol (65%) than with verinurad (51%) or allopurinol (43%) alone. Compared with the baseline rate, the maximum rate of uric acid excreted in urine was +56% with verinurad, -46% with allopurinol, and unchanged with verinurad + allopurinol. No serious AEs, discontinuations due to AEs, or clinically significant laboratory abnormalities were noted. Despite decreased systemic exposure of allopurinol and oxypurinol in the presence of verinurad, the combination resulted in greater serum urate reduction compared with either drug alone and was well tolerated at the studied doses.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Concomitant Multiple Dose Administration of Verinurad (RDEA3170) and Allopurinol in Adult Male Subjects With Gout.

Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000 mg calcium carbonate or 1600 mg magnesium hydroxide/1600 mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400 mg oral lesinurad. Study 2 evaluated low doses of antacids (1250 mg calcium carbonate or 800 mg magnesium hydroxide/800 mg aluminum hydroxide) on the PK and PD of 400 mg lesinurad. Food did not alter the plasma AUC of lesinurad and only reduced its Cmax by 18%. In the fasted conditions, high-dose calcium carbonate reduced the Cmax and AUC of lesinurad by 54% and 38%, respectively, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced Cmax and AUC by 36% and 31%, respectively. Food enhanced the maximum serum urate (sUA)-lowering effect of lesinurad by approximately 20% despite reducing the Cmax of lesinurad. High-dose calcium carbonate decreased the urate-lowering effect approximately 20% in the first 6 hours, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced the effect by 26%. Low-dose calcium carbonate or magnesium hydroxide/aluminum hydroxide in the presence of food did not significantly affect plasma lesinurad Cmax and AUC or the sUA lowering and renal handling of uric acid. In summary, study results suggest food did not meaningfully alter lesinurad PK and PD. High doses of antacids reduced lesinurad AUC up to 40% and reduced the lesinurad uric acid-lowering effect.

Effects of Food and Antacids on Pharmacokinetics and Pharmacodynamics of Lesinurad, a Selective Urate Reabsorption Inhibitor.

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Papers

Pharmacokinetics, Pharmacodynamics, and Tolerability of Concomitant Administration of Verinurad and Febuxostat in Healthy Male Volunteers.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Concomitant Multiple Dose Administration of Verinurad (RDEA3170) and Allopurinol in Adult Male Subjects With Gout.

Effects of Food and Antacids on Pharmacokinetics and Pharmacodynamics of Lesinurad, a Selective Urate Reabsorption Inhibitor.