Gout is the most common form of inflammatory arthritis and is a multifactorial disease typically characterized by hyperuricemia and monosodium urate crystal deposition predominantly in, but not limited to, the joints and the urinary tract. The prevalence of gout and hyperuricemia has increased in developed countries over the past two decades and research into the area has become progressively more active. We review the current field of knowledge with emphasis on active areas of hyperuricemia research including the underlying physiology, genetics and epidemiology, with a focus on studies which suggest association of hyperuricemia with common comorbidities including cardiovascular disease, renal insufficiency, metabolic syndrome and diabetes. Finally, we discuss current therapies and emerging drug discovery efforts aimed at delivering an optimized clinical treatment strategy.

/pdf/physiology-of-hyperuricemia-and-urate-lowering-treatments-16dj1wiipx.pdf

Physiology of Hyperuricemia and Urate-Lowering Treatments.

Purine metabolism in the circulatory system yields uric acid as its final oxidation product, which is believed to be linked to the development of gout and kidney stones. Hyperuricemia is closely correlated with cardiovascular disease, metabolic syndrome, and chronic kidney disease, as attested by the epidemiological and empirical research. In this review, we summarize the recent knowledge about hyperuricemia, with a special focus on its physiology, epidemiology, and correlation with cardiovascular disease. This review also discusses the possible positive effects of treatment to reduce urate levels in patients with cardiovascular disease and hyperuricemia, which may lead to an improved clinical treatment plan.

Hyperuricemia and Cardiovascular Disease.

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.

This article aims to critically review the evidence on the available therapeutic strategies for the treatment of hyperuricemia. For this reason, several papers were reviewed. Xanthine oxidase inhibitors are the safest and most effective uric acid lowering drugs for the management of chronic hyperuricemia, while the efficacy of uricosuric agents is strongly modulated by pharmacogenetics. Emergent drugs (lesinurad, peglotidase) were found to be more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials so that further well-designed clinical research is needed to deepen their efficacy and safety profile.

https://www.mdpi.com/1648-9144/57/1/58/pdf

Therapeutic Strategies for the Treatment of Chronic Hyperuricemia: An Evidence-Based Update

Introduction: The significant proportion of gout patients not reaching serum urate levels below 6.0 mg/dL and the debated pathogenicity of hyperuricemia (HU) itself motivate investigators to develo...

Investigational drugs for hyperuricemia, an update on recent developments.

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.

/pdf/pharmacokinetics-pharmacodynamics-and-tolerability-of-2xxek17mlr.pdf

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

Lesinurad is a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors (XOIs). Open-label pharmacokinetic studies were performed in volunteers or subjects with hyperuricemia (serum uric acid ≥ 8 mg/dL) to investigate interactions of lesinurad (with and without concurrent XOIs) with colchicine and 2 nonsteroidal anti-inflammatory drugs: naproxen and indomethacin. Colchicine studies included consecutive 7-day treatment periods of (1) allopurinol 300 mg, allopurinol 300 mg plus lesinurad 400 or 600 mg, and continued lesinurad 400 or 600 mg; or (2) febuxostat 40 or 80 mg, febuxostat 40 or 80 mg plus lesinurad 400 mg, and continued febuxostat 40 or 80 mg plus lesinurad 600 mg. Naproxen and indomethacin studies included lesinurad 400 mg on day 1, naproxen 250 mg twice daily or indomethacin 25 mg twice daily on days 2-6, and lesinurad 400 mg plus continued naproxen or indomethacin on days 7-13 and the morning of day 14. Lesinurad did not alter the pharmacokinetics of naproxen and modestly altered exposure to colchicine (AUC decrease of ≤ 25%) and indomethacin (AUC increase of ∼35%). Indomethacin did not alter the pharmacokinetics of lesinurad, whereas naproxen modestly decreased the Cmax of lesinurad by ∼27%.

Evaluation of Pharmacokinetic Interactions Between Lesinurad, a New Selective Urate Reabsorption Inhibitor, and Commonly Used Drugs for Gout Treatment

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Papers

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

Evaluation of Pharmacokinetic Interactions Between Lesinurad, a New Selective Urate Reabsorption Inhibitor, and Commonly Used Drugs for Gout Treatment