Pharmacokinetics, pharmacodynamics, and safety of verinurad with and without allopurinol in healthy Asian, Chinese, and non‐Asian participants

Abstract

Verinurad is a selective inhibitor of uric acid transporter 1 (URAT1). Here, we assessed the safety, pharmacokinetics, and pharmacodynamics of verinurad + allopurinol and verinurad monotherapy in healthy participants. Studies 1 (NCT03836599) and 2 (NCT02608710) were randomized Phase 1 studies. In Study 1, 12 healthy Asian participants received 24 mg verinurad + 300 mg allopurinol or placebo, and 9 healthy Chinese participants received 12 mg verinurad + 300 mg allopurinol. In Study 2, 24 healthy non‐Asian male participants received 12 mg verinurad. Safety analyses included assessment of adverse events (AEs). Pharmacokinetic parameters included maximum concentration (Cmax) and area under plasma concentration‐time curve (AUC) over 24 h (AUCτ). Pharmacodynamic parameters included percentage change from baseline (day –1) in serum uric acid (sUA) and urinary uric acid (uUA). There were no serious AEs or deaths in either study. In Study 1, steady‐state geometric mean (gCV%) Cmax and AUCτ values of verinurad after 7 days’ dosing were 73.6 (29.0) ng/mL and 478 (18.4) ng·h/mL, respectively, in healthy Asian participants, and 42.0 (40.1) ng/mL and 264 (36.1) ng·h/mL, respectively, in healthy Chinese participants; in Study 2, gCV% values were 36.3 (36.5) ng/mL and 271 (31.0) ng·h/mL, respectively. sUA decreased and uUA excretion increased compared with baseline following verinurad + allopurinol (Study 1) or verinurad (Study 2). When accounting for dose, the steady‐state pharmacokinetics of verinurad following multiple dosing were comparable between healthy Asian and Chinese participants and healthy non‐Asian participants. Verinurad treatments were well tolerated, including at higher verinurad exposures than previously evaluated after repeated dosing.

Verinurad does not prolong QTc interval: a thorough QT study using concentration–QTc modelling

“…Details of the analytical methods have been published previously 11,17 . PK parameters were derived using non‐compartmental methods, with Phoenix WinNonlin version 8.1 (Pharsight Corporation, Mountain View, CA, USA) 10 …”

“…allopurinol or febuxostat), which decreases production and consequently reduces the peak urinary excretion of UA. 8,9 The extended-release capsule of verinurad is characterized by prolonged absorption, with the maximum plasma concentration (C max ) occurring at 4 h. 10 Verinurad shows dose-proportional exposure with minimal accumulation. The half-life of verinurad is approximately 13 h in healthy subjects and a steady state is achieved within a few days of dosing.…”

Combination Treatment with Verinurad and Allopurinol in CKD

“…When verinurad was combined with the xanthine oxidase inhibitor febuxostat or allopurinol, verinurad decreased serum urate levels by up to 80%. [12][13][14] Post hoc analysis of the CITRINE study in 60 participants with type 2 diabetes and elevated albuminuria demonstrated that after 12 weeks of treatment, verinurad in combination with febuxostat compared with placebo reduced serum urate by 57% (95% confidence interval [CI], 48% to 64%) and albuminuria by 39% (90% CI, 4 to 62). 12 Since treatment effects to reduce albuminuria by at least 25% have been associated with long-term kidney protection, 15 this post hoc analysis suggested the potential of verinurad in combination with a xanthine oxidase inhibitor to reduce albuminuria and the risk of kidney failure.…”

“…When verinurad was combined with the xanthine oxidase inhibitor febuxostat or allopurinol, verinurad decreased serum urate levels by up to 80%. 12–14…”