The Pharmacodynamics, Pharmacokinetics, and Safety of Arhalofenate-febuxostat Combination in the Treatment of Gout-related Hyperuricemia

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SCIENCE
The Pharmacodynamics, Pharmacokinetics, and Safety of Arhalofenate-febuxostat Combination in the Treatment of Gout-related Hyperuricemia
Key Take-Away: 

Arhalofenate (ARH) and Febuxostat (FBX) reported to lower the serum uric acid (SUA) by complementary mechanisms. The combination provided greater decrease than monotherapy of each drug alone. The combination was appeared well tolerated and safe.

The most usual form of inflammatory arthritis is gout. As per the recent guidelines, a xanthine oxidase inhibitor as urate-lowering therapy (ULT) must be recommended to bring serum uric acid (SUA) to the target range of < 6 mg/dL

ABSTRACT: 
Background: 

The most usual form of inflammatory arthritis is gout. As per the recent guidelines, a xanthine oxidase inhibitor as urate-lowering therapy (ULT) must be recommended to bring serum uric acid (SUA) to the target range of < 6 mg/dL. Most of the patients do not seem to achieve their SUA targets with the commonly prescribed doses of xanthine oxidase inhibitors. Addition of uricosuric is often recommended when the target is not achieved.

Another issue is the worsening of gout flares with ULT treatment. This ironic effect is one of the most important barriers to the adherence to ULT approach. Therefore, it is recommended to take anti-inflammatory compounds such as colchicine, systemic corticosteroids, or nonsteroidal anti-inflammatory drugs (NSAID) while initiating ULT. These anti-inflammatory agents are poorly tolerated, potentially unsafe, and contraindicated in many patients with gout. Thus, there is a pressing need for new gout treatments that can provide better SUA and flare controls.

Arhalofenate (ARH) is a novel dual-acting drug that outlines a new class of gout therapy called urate-lowering anti-flare therapy. It’s SUA lowering action is due to the blocking of tubular reabsorption of uric acid (UA) by URAT-1 and further reduces gout flares by blocking the urate crystal-stimulated release of interleukin 1β, the key cytokine that triggers gout flares. Thus, because of the dual action, ARH has the potential to streamline the treatment of gout and improve its management.

Rationale behind research

  • The recent study was conducted to meet the great unmet need of developing new gout treatments that provide better SUA and flare controls.

Objective

To evaluate the SUA-lowering effect of ARH when combined with FBX, and to evaluate the potential for a drug interaction and to assess the tolerability and safety of both drugs when used alone and in combination.

Methods: 

 

  • Study outcomes
  • Primary objectives: The primary objectives were to assess the SUA reductions with ARH (600 mg and 800 mg) when combined with FBX (40 mg and 80 mg) as both absolute and percentage reductions from baseline, the percentage of patients achieving the target SUA of < 6 mg/dL, < 5 mg/dL, and < 4 mg/dL, and  the potential for any significant interaction between ARH and FBX.
  • Secondary objectives: The secondary objectives were to assess the SUA reductions for ARH 600 mg and 800 mg and FBX 40 mg and 80 mg as monotherapies, and the safety and tolerability of ARH when combined with FBX, including serious adverse events (SAE), discontinuations for safety, treatment-emergent adverse events (TEAE), and changes in laboratory variables. 
Results: 

 

Outcomes

Baseline characteristics: Demographics and baseline characteristics were similar between cohorts.

Primary outcomes: The largest decrease in SUA was observed with the ARH 800 mg + FBX 80 mg combination at week 4 with absolute and percent changes from baseline of 5.8 mg/dL and 63%, respectively. These changes were significantly greater than those for ARH or FBX alone (weeks 2 and 6, respectively; P< 0.0001). The mean SUA changes from baseline in the ARH 600 mg + FBX 80 mg and the ARH 800 mg + FBX 40 mg combinations were similar at week 3 (–54% and –55%, respectively). All 14 subjects (100%) treated with ARH 800 mg + FBX 80 mg achieved an SUA of <6.0 mg/dL and 13/14 subjects (93%) achieved an SUA of <5 mg/dL. Eleven out of 14 subjects (79%) achieved the target of < 4 mg/dl (P< 0.05). Overall, 100% of subjects receiving ARH 800 mg, with either 40 mg or 80 mg of FBX, reached an SUA of <6.0 mg/dL. 

Table 1: Percentage of patients achieving target SUA

Secondary outcomes: For patients receiving ARH 800 mg as monotherapy, SUA decreased gradually over the first 14 days with a decrease from baseline of 1.88 mg/dL. There were minimal intra-day fluctuations in mean SUA when ARH was administered either as monotherapy or in combination with FBX. Treatment with ARH 800 mg increased the mean FEUA during each period on days 3, 7, and 14 (4.5% to 6.5%, P< 0.001 overall). Treatment with febuxostat monotherapy decreased FEUA (3.1%) relative to baseline, whereas its co-administration with ARH resulted in an increase in FEUA to 4.8%. The ratio of AUC(0-T) geometric means of the combination to ARH alone was 108% (90% CI 89–131). The serum half-life of ARH acid is about 50 h and sampling was conducted for only 24 h. Therefore, the half-life was estimated at 77 h. In vivo inhibition of xanthine oxidase increases the concentrations of its substrates xanthine and hypoxanthine. Also. there were no deaths and SAE reported. 

Conclusion: 

The study showed that the combination of ARH and FBX has potent SUA-lowering activity that is superior to that of each drug alone. Combination of ARH 800 mg with either 40 mg or 80 mg of FBX enabled all patients to reach an SUA of <6 mg/dL, the recommended target for patients with uncomplicated gout. Further, when ARH 800 mg was administered with FBX 80 mg, 93% achieved an SUA of <5 mg/dL and 79% an SUA of <4 mg/dL. Achieving a lower SUA target of <5 mg/dL is recommended for gout patients with more advanced disease and large UA burden, clinically exemplified by tophi.

Studies have shown that most patients with gout do not achieve their recommended SUA goals. Many continue to experience flare attacks and further joint damage with continued deposition of urate crystals. A significant barrier to the management of gout is also because of the paradoxical increase in flares when initiating treatment with a ULT. This particular study showed that patients with gout treated with combinations of ARH (600 mg or 800 mg) and FBX (40 mg or 80 mg) experienced potent reductions in SUA, enabling all patients to achieve the recommended goal of < 6 mg/dL. The combination of ARH 800 mg and FBX 80 mg was particularly effective, allowing the great majority of patients to reduce their SUA below 5 mg/dL, a goal recommended for patients with tophaceous gout. The combination was well tolerated and appeared safe.

The Journal of Rheumatology 2017; 44:3

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