The Pharmacodynamics, Pharmacokinetics, and Safety of Arhalofenate in Combination with Febuxostat When Treating Hyperuricemia Associated with Gout

• Published in: Journal of rheumatology 2017-03, Vol.44 (3), p.374-379
• Main Authors: Steinberg, Alexandra S, Vince, Bradley D, Choi, Yun-Jung, Martin, Robert L, McWherter, Charles A, Boudes, Pol F
• Format: Article
• Language: English
• Subjects: Acetamides - adverse effects; Acetamides - pharmacology; Acetamides - therapeutic use; Adolescent; Adult; Aged; Drug Administration Schedule; Drug Therapy, Combination; Febuxostat - adverse effects; Febuxostat - pharmacology; Febuxostat - therapeutic use; Female; Gout - blood; Gout - drug therapy; Gout Suppressants - adverse effects; Gout Suppressants - pharmacology; Gout Suppressants - therapeutic use; Humans; Hyperuricemia - blood; Hyperuricemia - drug therapy; Male; Middle Aged; Phenylacetates - adverse effects; Phenylacetates - pharmacology; Phenylacetates - therapeutic use; Treatment Outcome; Uric Acid - blood; Uricosuric Agents - adverse effects; Uricosuric Agents - pharmacology; Uricosuric Agents - therapeutic use; Young Adult
• ISSN: 0315-162X; 1499-2752
• DOI: 10.3899/jrheum.161062

Arhalofenate (ARH), in development for gout, has uricosuric and anti-flare activities. ARH plus febuxostat (FBX) were evaluated in subjects with gout for serum uric acid (SUA) lowering, drug interaction, and safety. Open phase II trial in gout volunteers (NCT02252835). Cohort 1 received ARH 600 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 80 mg followed by 40 mg. FBX 40 mg was continued alone for 2 weeks. Cohort 2 received ARH 800 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 40 mg followed by 80 mg. FBX 80 mg was continued alone for 2 weeks. SUA, its fractional excretion (FEUA), and plasma oxypurines were assessed. Pharmacokinetics of FBX and ARH were determined alone and in combination for cohort 2. Baseline mean SUA was 9.4 mg/dl for cohort 1 (n = 16) and 9.2 mg/dl for cohort 2 (n = 16). The largest SUA decrease (63%) was observed with ARH 800 mg + FBX 80 mg, with all subjects reaching SUA < 6 mg/dl and 93% < 5 mg/dl. The area under the curve (AUC) of ARH acid + FBX/ARH acid was 108%. The AUC of FBX + ARH acid/FBX was 87%. As expected, FBX increased oxypurines and increases were unaffected by ARH co-administration. Baseline FEUA were low (3.5%-4.6%) and ARH increased them toward normal without overexcretion of UA. ARH was well tolerated and appeared safe. ARH and FBX lowered SUA by complementary mechanisms. The combination provided greater decreases than each drug alone. The combination was well tolerated and appeared safe. NCT02252835.