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

Figures & data

Table 1 Demographic and baseline characteristics

	Single ascending doses		Multiple ascending doses
	Pooled placebo (N=12)	Pooled verinurad (N=36)	Pooled placebo (N=8)	Pooled verinurad (N=25)
Age, years	30 (10.3)	26 (6.9)	32 (8.0)	31 (8.7)
Body weight, kg	77.4 (8.2)	76.9 (8.9)	81.5 (7.0)	77.7 (12.2)
Body mass index, kg/m^2	24.5 (3.1)	24.3 (2.6)	26.1 (2.8)	24.5 (3.3)
Race, n (%)
Black	0 (0.0)	1 (2.8)	1 (12.5)	2 (8.0)
White	11 (91.7)	32 (88.9)	7 (87.5)	21 (84.0)
Asian	1 (8.3)	1 (2.8)	0 (0.0)	1 (4.0)
Ethnicity, n (%)
Not Hispanic or Latino	12 (100)	36 (100)	8 (100)	25 (100)

Note: Data are mean (SD) unless otherwise noted.

Table 2 Summary of verinurad plasma PK following single ascending doses in fasted and fed states

Dose, mg	Food	Tmaxa, hour	Cmax, ng/mL	AUC0–∞, ng⋅hour/mL	t1/2, hour	CL/F, L/hour	Vss/F, L
2	Fasted	0.50 (0.25–0.50)	36.4 (22.4–59.2)	45.0 (34.7–58.3)	12.1 (7.61–19.2)	44.5 (34.3–57.7)	394 (227–683)
5	Fasted	0.63 (0.50–0.75)	72.9 (53.7–98.9)	121 (108–135)	14.2 (10.7–18.8)	41.4 (37.0–46.3)	419 (312–562)
	Fed	1.25 (0.75–2.50)	45.7 (34.5–60.6)	92.8 (71.8–120)	12.7 (9.73–16.7)	53.9 (41.7–69.6)	625 (455–859)
	GMRb		62.7% (46.8%–84.1%)	76.8% (63.1%–93.6%)
20	Fasted	0.50 (0.25–1.50)	384 (268–550)	540 (469–623)	10.9 (6.15–19.2)	37.0 (32.1–42.7)	328 (201–535)
	Fed	1.25 (1.00–2.50)	181 (92.1–357)	415 (282–611)	13.8 (7.88–24.0)	48.2 (32.7–70.8)	531 (292–964)
	GMRb		47.2% (27.5%–81.1%)	76.8% (57.5%–103%)
40	Fasted	0.75 (0.25–1.00)	760 (493–1,170)	1,270 (873–1,840)	9.51 (7.81–11.6)	31.6 (21.7–45.8)	280 (143–549)

Notes:

a T_max presented as median (range).

b Geometric mean ratio (GMR, %) (90% CI) (fed/fasted). Other data are geometric mean (95% CI).

Abbreviations: AUC_0–∞, area under plasma concentration–time curve from 0 to infinity; PK, pharmacokinetics; C_max, maximum observed plasma concentration; t_1/2, terminal half-life; T_max, time to maximum observed plasma concentration; CL/F, apparent total clearance, corrected by bioavailability; V_ss/F, volume of distribution at equilibrium, corrected by bioavailability.

Figure 1 Mean (SE) verinurad plasma concentration–time profiles following single ascending doses in fasted and fed states (A) and following multiple daily ascending doses in the fasted state (B).

Abbreviation: SE, standard error.

Table 3 Summary of verinurad plasma PK and urinary fractional excretion of verinurad following the first and tenth doses in the fasted state

Dose, mg	Day	Tmaxa, hour	Cmax, ng/mL	AUC0–24, ng⋅hour/mL	fe0–24, %
1	1	0.50 (0.25–0.50)	13.5 (10.7–17.0)	15.1 (13.1–17.5)	1.92 (1.45–2.53)
	10	0.50 (0.25–1.00)	14.4 (11.8–17.6)	20.1 (18.3–22.1)	2.00 (1.47–2.72)
5	1	0.50 (0.50–7.50)	84.8 (49.9–144)	94.1 (69.2–128)	1.75 (0.86–3.57)
	10	0.75 (0.50–1.00)	73.6 (44.0–123)	116 (93.9–144)	2.81 (1.71–4.62)
10	1	0.50 (0.50–1.00)	121 (79.1–184)	199 (173–229)	2.31 (1.73–3.08)
	10	1.00 (0.50–2.50)	124 (88.4–175)	237 (194–291)	2.86 (2.24–3.64)

Notes:

a Median (range). Other data are geometric mean (95% CI).

Abbreviations: AUC_0–24, area under the concentration–time curve from time 0 up to 24 hours post dose; PK, pharmacokinetics; C_max, maximum observed plasma concentration; fe_0–24, fraction of the dose excreted in urine unchanged from time 0 to 24 hours post dose; T_max, time to maximum observed plasma concentration.

Figure 2 Dose proportionality of verinurad C_max and AUC_0-∞.

Abbreviations: AUC, area under the plasma concentration–time curve; C_max, maximum observed plasma concentration.

Figure 3 Mean (SE) percent change from baseline in sUA–time profiles following single dose in the fasted or fed state (A) and once-daily multiple (B) doses of verinurad in the fasted state.

Abbreviations: SE, standard error; sUA, serum urate.

Figure 4 Mean (SE) Ae_UR (A and B) and FEUA (C and D) by urine collection interval following single ascending doses (A and C) or once-daily multiple ascending doses (B and D) of verinurad.

Abbreviations: Ae_UR, amount of uric acid recovered in urine; FEUA, fractional excretion of uric acid; SE, standard error.

Table 4 Summary of treatment-emergent AEs following single or multiple ascending doses of verinurad

	Single ascending dose		Multiple ascending dose
	Pooled placebo (N=12)	Pooled verinurad (N=36)	Pooled placebo (N=8)	Pooled verinurad (N=25)
Any AE, n (%) (events)	1 (8.3) (1)	6 (16.7) (13)	4 (50) (10)	18 (72) (40)
Mild severity	1 (8.3) (1)	6 (16.7) (12)	4 (50) (8)	18 (72) (37)
Moderate severity	0	1 (2.8) (1)	1 (12.5) (2)	3 (12.0) (3)
Severe/life-threatening	0	0	0	0
AE possibly related to study drug, n (%) (events)	0	4 (11.1) (9)	3 (37.5) (6)	8 (32.0) (19)
Mild severity	0	4 (11.1) (8)	3 (37.5) (6)	8 (32.0) (18)
Moderate severity	0	1 (2.8) (1)	0	1 (4.0) (1)
Severe/life-threatening	0	0	0	0

Abbreviation: AE, adverse event.