Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers

Figures & data

Table 1 Demographic and baseline characteristics at screening by renal function status and lesinurad dose

	Lesinurad 200 mg dose			Lesinurad 400 mg dose
	Normal renal function (N=6)	Mild renal impairment (N=8)	Moderate renal impairment (N=10)	Normal renal function (N=6)	Moderate renal impairment (N=6)	Severe renal impairment (N=6)
Age (years, mean)	61.2 (56–68)	68.5 (54–74)	64.3 (41–79)	53 (50–57)	52.7 (42–59)	58.7 (48–73)
Body weight (kg, mean)	93.1 (82.3–108.6)	84.8 (74.1–103.8)	97.6 (74.8–124.2)	96.5 (82.9–108.8)	104.7 (71.3–123)	89.5 (68.1–119.5)
BMI (kg/m^2, mean)	30 (28.5–31.5)	28.6 (24.2–38.2)	31.2 (22.7–39.2)	30.2 (24–34)	34 (27–38)	29.7 (24–40)
Gender, males, n (%)	4 (66.7)	5 (62.5)	9 (90)	6 (100)	6 (100)	6 (100)
Race
Black, n (%)	0	0	3 (30)	0	4 (66.7)	3 (50.0)
White, n (%)	6 (100)	8 (100)	7 (70)	6 (100)	2 (33.3)	3 (50.0)
Ethnicity: not Hispanic or	6 (100)	8 (100)	10 (100)	5 (83.3)	6 (100)	6 (100)
Latino, n (%)
Plasma protein binding (%, mean)	98.6 (98.5–98.7)	98.5 (98.2–98.6)	98.4 (97.7–98.8)	99.0 (98.9–99.2)	98.8 (98.5–98.9)	98.6 (98.3–98.9)
Baseline sUA (mg/dL, mean)	6.8 (4.9–8.9)	6.7 (5.0–9.3)	8.8 (6.3–13.8)	5.8 (4.0–7.9)	9.3 (7.5–14.2)	9.2 (7.4–11.2)

Note: Data are mean (min, max) or n (%).

Abbreviations: BMI, body mass index; sUA, serum uric acid.

Table 2 Geometric mean (95% CI) plasma and urine pharmacokinetics of lesinurad by renal function status and lesinurad dose

Renal function	Lesinurad dose (mg)	N	Urine pharmacokinetics
			Tmaxa	Cmax	AUC0–∞	CL/F	Ae0–72	fe0–72	CLR0–72
			(h)	(µg/mL)	(µg⋅h/mL)	(L/h)	(mg)	(%)	(mL/min)
Normal	200	6	1.25 (0.750–2.00)	8.12 (5.55–11.9)	31.8 (21.5–46.9)	6.30 (4.26–9.30)	34.2 (24.2–48.4)	17.1 (12.1–24.2)	18.0 (10.2–31.7)
	400	6	2.00 (1.50–4.00)	15.9 (14.3–17.8)	55.0 (40.5–74.6)	7.28 (5.36–9.89)	84.0 (48.2–146)	21.0 (12.1–36.5)	25.6 (14.4–45.5)
Mild renal impairment	200	8	0.750 (0.750–1.50)	11.5 (10.1–13.0)	42.6 (35.0–51.9)	4.69 (3.86–5.72)	33.5 (24.1–46.5)	16.7 (12.0–23.2)	13.3 (9.10–19.3)
Moderate renal impairment	200	10	1.25 (0.500–6.00)	9.32 (6.51–13.4)	52.4 (37.3–73.5)	3.82 (2.72–5.36)	10.7a (4.10–27.9)	5.35a (2.05–13.9)	3.24a (1.12–9.36)
	400	6	3.00 (1.50–6.00)	15.1 (9.24–24.6)	84.5 (69.8–102)	4.73 (3.91–5.73)	33.3 (15.3–72.6)	8.32 (3.81–18.2)	6.59 (3.03–14.4)
Severe renal impairment	400	6	3.00 (0.750–6.00)	17.9 (15.1–21.2)	111 (67.3–183)	3.60 (2.18–5.94)	20.7 (9.32–46.0)	5.17 (2.33–11.5)	3.12 (1.19–8.22)

Notes:

a n=9. Data are geometric mean (95% CI) unless otherwise noted.

Abbreviations: T_max, median (range). T_max, time to C_max; C_max, maximum observed plasma concentration; AUC_0–∞, area under the plasma concentration–time curve from zero to infinity; CL/F, apparent oral clearance; A_e, amount of lesinurad excreted unchanged in urine over a time interval; f_e, fraction of the lesinurad dose excreted unchanged in urine following dosing; CL_R, renal clearance of lesinurad.

Table 3 Geometric mean ratios (90% CI) of plasma and urine lesinurad pharmacokinetic parameters by renal function status and lesinurad dose

Comparison	Lesinurad dose (mg)	Plasma pharmacokinetics		Urine pharmacokinetics
		Cmax	AUC0–∞	Ae0–72	CLR0–72
Mild renal impairment vs normal renal function	200	141% (110%–181%)	134% (101%–179%)	97.9% (68.7%–140%)	73.7% (46.0%–118%)
Moderate renal impairment vs normal renal function	200	115% (75.7%–174%)	165% (111%–246%)	31.3% (12.3%–79.5%)	18.0% (6.24%–51.8%)
	400	94.8% (66.5%–135%)	154% (119%–198%)	39.7% (20.2%–77.9%)	25.8% (13.0%–51.0%)
Severe renal impairment vs normal renal function	400	112% (97.5%–130%)	202% (134%–306%)	24.7% (12.4%–48.9%)	12.2% (5.52%–27.0%)

Abbreviations: C_max, maximum observed plasma concentration; AUC_0–∞, area under the plasma concentration–time curve from zero to infinity; A_e0–72, amount of lesinurad excreted unchanged in urine from zero to 72 hours; CL_R, renal clearance of lesinurad.

Figure 1 Median plasma concentration profiles of (A) lesinurad 200 mg or (B) lesinurad 400 mg in subjects with various degrees of renal function (semi-log scale).

Figure 2 The relationship between renal function status and lesinurad PK parameters.

Notes: 200 mg, lesinurad 200 mg; 400 mg, lesinurad 400 mg.
Abbreviations: PK, pharmacokinetics; AUC, area under the plasma concentration–time curve; CL, clearance of lesinurad; C_max, maximum observed plasma concentration.

Figure 3 Mean (SE) percent change from baseline (time-matched Day 1) in serum concentrations of uric acid within 24 hours post-dose in subjects with normal renal function, mild, moderate, or severe renal impairment following a single dose of (A) lesinurad 200 mg or (B) lesinurad 400 mg.

Notes: ○, normal function; ▲, mild impairment; ♦, moderate impairment; ■, severe impairment.
Abbreviation: SE, standard error.

Table 4 Mean (SE) urinary uric acid pharmacodynamic parameters by renal function status and lesinurad dose

Renal function category	Lesinurad dose (mg) (N)	AeUR (mg)				CLUR (mL/min)				FEUA (%)
		Baseline		Treatment		Baseline		Treatment		Baseline		Treatment
		0–6 h	0–24 h	0–6 h	0–24 h	0–6 h	0–24 h	0–6 h	0–24 h	0–6 h	0–24 h	0–6 h	0–24 h
Normal function	200 (6)	209 (105)	721 (149)	441 (186)	854 (259)	8.4 (4.2)	7.6 (1.2)	20 (7.0)	11 (2.6)	6.7 (1.4)	5.9 (1.7)	16 (3.7)	9.3 (2.3)
	400 (6)	196 (23)	654 (54)	512 (305)	1,216 (303)	9.9 (3.4)	8.6 (2.3)	27 (15)	18 (1.8)	5.7 (1.5)	5.9 (0.9)	15 (6.0)	12 (2.5)
Mild impairment	200 (8)	144 (50)	510 (144)	276 (192)	545 (306)	6.3 (2.7)	5.4 (1.7)	14 (10)	7.3 (4.5)	7.8 (1.5)	6.5 (1.2)	16 (11)	9.3 (5.7)
Moderate impairment	200 (10)	117 (89)	383 (260)	178 (151)	467 (256)	4.1 (3.8)	3.3 (2.9)	6.7 (7.2)	4.4 (3.5)	6.1 (3.2)	5.9 (3.0)	12 (6.8)	8.9 (3.8)
	400 (6)	127 (21)	503 (141)	234 (163)	620 (314)	4.0 (1.1)	3.9 (1.5)	7.5 (5.1)	5.3 (2.1)	6.4 (3.5)	5.9 (2.7)	12 (7.0)	9.2 (3.5)
Severe impairment	400 (6)	74 (21)	305 (54)	117 (69)	358 (94)	2.3 (0.9)	2.5 (0.5)	3.7 (2.4)	3.1 (1.2)	8.0 (4.4)	8.9 (4.6)	15 (7.5)	13 (7.4)

Abbreviations: Ae_UR, amount of uric acid recovered in urine; CL_UR, renal clearance of uric acid; FEUA, fractional excretion of uric acid; h, hours; SE, standard error.