Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Verinurad, a Selective Uric Acid Reabsorption Inhibitor

Abstract

Background and ObjectiveVerinurad (RDEA3170) is a high-affinity, selective URAT1 transporter inhibitor in development for treating gout and asymptomatic hyperuricemia. This Phase I, single-dose study investigated the pharmacokinetics, pharmacodynamics, and safety of verinurad in adults with renal impairment and controls with normal renal function.MethodsMales aged 18–85 years were enrolled with serum urate (sUA) 4.5–10 mg/dl and creatinine clearance 60– < 90, 30– < 60, 15– < 30, or ≥ 90 ml/min (mild, moderate, severe renal impairment and controls, respectively; n = 7/8). Verinurad 15 mg was administered orally under fasted conditions. Serial plasma/serum and urine samplings were 30 min pre-dose to 72 h post-dose.ResultsCompared to controls, verinurad maximum observed plasma concentration increased by 53, 73, and 128% and area under the concentration-time curve increased by 24, 148, and 130%, in subjects with mild, moderate, and severe renal impairment, respectively; renal clearance decreased by 5, 42, and 79%. Exposures of major verinurad metabolites also increased with increasing renal impairment. Verinurad decreased sUA in all groups, with greater maximal changes in control and mild renal impairment than moderate and severe impairment groups (− 38.3, − 36.9, − 20.5, − 12.6%, respectively). There were no adverse event-related withdrawals or clinically meaningful changes in laboratory values.ConclusionExposures of verinurad and metabolites increased with decreasing renal function. Consistent with the renal-dependent mechanism of action of verinurad, increasing severity of renal impairment was associated with decreased sUA lowering. Verinurad safety assessments were similar regardless of renal impairment. Continued investigation of verinurad is warranted in patients with gout and renal impairment.ClinicalTrials.gov identifierNCT02219516.

A semi-mechanistic exposure–response model to assess the effects of verinurad, a potent URAT1 inhibitor, on serum and urine uric acid in patients with hyperuricemia-associated diseases

“…For example, one limitation of the current work is the inclusion of a limited number of patients with severe renal impairment (eGFR \ 30 mL/ min/1.73 m 2 ). Therefore, this model may not reflect the exposure-response relationship in patients with severely impaired kidney function, as our current model overpredicts sUA and uUA in the renal impairment study RDEA3170-108 [38]. One explanation for this overprediction may be a higher FEUA in renally impaired patients, which in turn affects sUA level and the effect of the treatment.…”

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

“…By comparison, among healthy Japanese male participants, C max and AUC τ values for verinurad of 38.2 ng/mL and 239 ng·h/mL, respectively, were observed on day 6 after QD dosing with 15 mg verinurad given as a modified‐release formulation, 14 which has a lower bioavailability compared with the formulation used in Studies 1 and 2. To put this into perspective, increased verinurad exposures have been observed in participants with renal impairment receiving 15 mg verinurad, with an increased C max of 73% and 128% and an increased AUC of 148% and 130% in participants with moderate and severe renal impairment, respectively, compared with normal renal function 16 . Given the potential for higher verinurad exposure in the target patient population, i.e.…”

“…Given the potential for higher verinurad exposure in the target patient population, i.e. those with reduced renal function, 16 assessment of higher exposures of verinurad than previously assessed during repeated dosing was therefore warranted. We observed no safety or tolerability concerns with dosing of up to 24 mg verinurad + 300 mg allopurinol in healthy Asian participants.…”

“…In healthy Chinese participants, sUA levels at screening (day -8) and baseline (day -1), respectively, were 5.64 mg/dL and 4.49 mg/dL with 12 mg verinurad + 300 mg allopurinol. Abbreviations: FEUA, fractional excretion of uric acid; SD, standard deviation; sUA, serum uric acid 16 Given the potential for higher verinurad exposure in the target patient population, i.e. those with reduced renal function, 16 assessment of higher exposures of verinurad than previously assessed during repeated dosing was therefore warranted.…”

“…Abbreviations: FEUA, fractional excretion of uric acid; SD, standard deviation; sUA, serum uric acid 16 Given the potential for higher verinurad exposure in the target patient population, i.e. those with reduced renal function, 16 assessment of higher exposures of verinurad than previously assessed during repeated dosing was therefore warranted. We observed no safety or tolerability concerns with dosing of up to 24 mg verinurad + 300 mg F I G U R E 4 Study 2: Mean (SD) observed (A) sUA and (B) FEUA following single doses and multiple doses of verinurad in healthy non-Asian participants.…”