Pharmacokinetics, pharmacodynamics, and tolerability of LC350189, a novel xanthine oxidase inhibitor, in healthy subjects

Figures & data

Figure 1 Uric acid formation.

Table 1 Summary of pharmacodynamic parameters for uric acid

Uric acid	Cmean,24 (mg/dL)			Change in Cmean,24 (%)		CLR (mL/min)
	Baseline	Day 1 (Day 8*)	Day 7	1 day (Day 8*)	Day 7	Baseline	Day 1 (Day 8*)	Day 7
SAD study
10 mg (n=6)	6.00 (0.94)	5.50 (1.00)	–	−8.7 (3.6)	–	7.1 (2.3)	6.5 (2.1)	–
25 mg (n=6)	6.59 (0.92)	5.58 (0.90)	–	−15.5 (4.3)	–	6.9 (1.6)	6.8 (1.3)	–
50 mg (n=8)	5.89 (1.16)	5.05 (1.25)	–	−15.2 (5.4)	–	7.6 (2.8)	6.8 (2.1)	–
100 mg (n=8)	5.71 (0.67)	4.64 (0.78)	–	−19.3 (5.3)	–	6.5 (1.9)	6.8 (1.8)	–
200 mg (n=8) (fasting)	6.75 (1.22)	5.25 (1.22)	–	−22.9 (4.7)	–	7.5 (1.4)	7.5 (1.6)	–
200 mg (n=8) (fed)*	–	4.80 (10.5)		−29.5 (4.3)		–	8.6 (1.8)
400 mg (n=8)	8.12 (1.55)	6.17 (1.44)	–	−24.4 (7.9)	–	6.1 (1.1)	6.7 (2.4)	–
600 mg (n=8)	7.63 (0.73)	5.22 (0.76)	–	−31.7 (6.8)	–	5.2 (1.1)	6.9 (1.5)	–
placebo (n=14)	6.38 (1.86)	6.49 (2.21)	–	0.8 (6.9)	–	7.6 (2.5)	7.4 (2.0)	–
MAD study
100 mg (n=8)	5.97 (1.18)	4.99 (1.01)	2.76 (0.62)	−16.5 (3.4)	−53.5 (5.7)	6.3 (1.7)	5.8 (0.8)	4.8 (0.9)
200 mg (n=8)	5.15 (0.99)	3.96 (0.97)	1.51 (0.35)	−24.2 (6.4)	−70.8 (2.3)	7.5 (2.5)	7.9 (2.6)	5.9 (1.4)
400 mg (n=8)	6.62 (0.91)	5.00 (0.73)	1.25 (0.22)	−24.5 (3.6)	−81.0 (3.1)	5.6 (1.0)	6.9 (0.9)	5.6 (1.0)
600 mg (n=8)	6.86 (1.55)	4.95 (1.48)	0.96 (0.36)	−29.1 (8.0)	−86.2 (4.3)	4.7 (2.2)	9.0 (5.6)	6.4 (2.9)
800 mg (n=6)	7.81 (0.84)	5.36 (0.77)	0.68 (0.23)	−31.4 (5.0)	−91.2 (3.0)	4.5 (1.8)	8.5 (1.5)	6.7 (1.7)
Febuxostat 80 mg (n=8)	7.24 (1.20)	6.04 (1.14)	2.99 (0.68)	−16.8 (2.8)	−58.8 (5.9)	4.7 (1.4)	4.9 (1.1)	4.3 (1.0)
Placebo (n=10)	6.13 (1.07)	6.24 (0.99)	6.13 (1.1)	2.1 (3.6)	0 (6.9)	6.4 (1.7)	6.9 (1.7)	6.9 (2.6)

Notes: All values are presented as mean (SD).

* Data of 200 mg dose group under fed condition; –, no data.

Abbreviations: C_mean,24, 24-hour mean serum concentrations of uric acid; CL_R, renal clearance of uric acid; min, minutes; SAD, single ascending dose; MAD, multiple ascending dose; SD, standard deviation.

Figure 2 Uric acid–time profile after administration of LC350189.

Notes: (A) SAD study, (B) food interaction study, and (C) MAD study. In (B), the uric acid change was calculated with 0 h of day 1 or day 8 as baseline.
Abbreviations: SAD, single ascending dose; MAD, multiple ascending dose; h, hours.

Figure 3 The box plots of the mean percentage changes in serum 24-hour mean concentration (C_mean,24) (A, C, and E) and the amount of uric acid, xanthine, and hypoxanthine excreted in urine (B, D, and F) vs dose following a single-dose (day 1) administration of LC350189.

Notes: The dots represent individual values. A line within the box marks the median, and the boundaries of the box indicate the 25th and 75th percentiles.

Figure 4 The box plots of the mean percentage changes in serum 24-hour mean concentration (C_mean,24) (A, C, and E) and the amount of uric acid, xanthine, and hypoxanthine excreted in urine (B, D, and F) vs dose following multiple-dose (day 7) administrations of LC350189 or febuxostat.

Notes: The dots represent individual values. A line within the box marks the median, and the boundaries of the box indicate the 25th and 75th percentiles.

Table 2 Summary of pharmacodynamic parameters for xanthine

Xanthine	Cmean,24 (mg/dL)			Change in Cmean,24 (%)		CLR (mL/min)
	Baseline	Day 1 (Day 8*)	Day 7	Day 1 (Day 8*)	Day 7	Baseline	Day 1 (Day 8*)	Day 7
SAD study
10 mg (n=6)	0.028 (0.011)	0.074 (0.006)	–	206.9 (132.6)	–	28.9 (19.4)	65.1 (14.3)	–
25 mg (n=6)	0.031 (0.009)	0.094 (0.010)	–	225.6 (123.9)	–	16.6 (6.7)	63.7 (5.0)	–
50 mg (n=8)	0.024 (0.005)	0.114 (0.008)	–	385.0 (87.9)	–	24.6 (7.6)	64.8 (7.2)	–
100 mg (n=8)	0.030 (0.006)	0.139 (0.015)	–	366.9 (69.5)	–	14.6 (4.5)	67.0 (12.6)	–
200 mg (n=8) (fasting)	0.021 (0.003)	0.162 (0.016)	–	697.6 (174.3)	–	26.8 (4.3)	75.4 (14.5)	–
200 mg (n=8) (fed)*	–	0.141 (0.015)		590.8 (132.9)		–	73.7 (22.1)
400 mg (n=8)	0.038 (0.006)	0.224 (0.029)	–	503.7 (16.4.3)	–	15.7 (4.5)	78.5 (19.5)	–
600 mg (n=8)	0.035 (0.014)	0.197 (0.022)	–	541.7 (216.3)	–	17.0 (10.5)	70.7 (20.9)	–
Placebo (n=14)	0.028 (0.007)	0.031 (0.010)	–	8.7 (23.1)	–	21.7 (8.6)	20.4 (10.5)	–
MAD study
100 mg (n=8)	0.036 (0.003)	0.138 (0.015)	0.156 (0.019)	291.9 (58.0)	344.1 (79.9)	15.1 (4.0)	61.8 (8.5)	57.0 (8.0)
200 mg (n=8)	0.044 (0.009)	0.169 (0.026)	0.221 (0.027)	289.4 (63.8)	418.1 (126.9)	12.9 (3.5)	78.8 (17.2)	82.1 (14.0)
400 mg (n=8)	0.036 (0.007)	0.192 (0.035)	0.249 (0.050)	450.6 (166.0)	611.3 (203.9)	15.3 (5.8)	66.0 (15.8)	70.8 (15.5)
600 mg (n=8)	0.045 (0.026)	0.195 (0.032)	0.262 (0.054)	419.1 (213.2)	617.2 (340.1)	12.4 (6.2)	62.3 (23.0)	66.4 (16.5)
800 mg (n=6)	0.032 (0.008)	0.185 (0.023)	0.295 (0.057)	495.0 (130.8)	846.7 (246.6)	11.6 (5.5)	68.7 (14.3)	74.7 (14.3)
Febuxostat 80 mg (n=8)	0.042 (0.009)	0.182 (0.036)	0.235 (0.067)	333.8 (60.4)	454.5 (92.3)	10.9 (4.2)	55.7 (16.6)	59.6 (12.7)
Placebo (n=10)	0.036 (0.008)	0.033 (0.009)	0.035 (0.007)	−8.3 (15.1)	−1.1 (16.3)	13.6 (4.7)	15.8 (6.8)	14.2 (4.2)

Notes: All values are presented as mean (SD).

* Data of 200 mg dose group under fed condition.

Abbreviations: C_mean,24, 24-hour mean serum concentrations of xanthine; CL_R, renal clearance of xanthine; min, minutes; SAD, single ascending dose; MAD, multiple ascending dose; SD, standard deviation.

Table 3 Summary of pharmacodynamic parameters for hypoxanthine

Hypoxanthine	Cmean,24 (mg/dL)			Change in Cmean,24 (%)		CLR (mL/min)
	Baseline	Day 1 (Day 8*)	Day 7	Day 1 (Day 8*)	Day 7	Baseline	Day 1 (Day 8*)	Day 7
SAD study
10 mg (n=6)	0.116 (0.058)	0.097 (0.020)	–	−4.6 (29.6)	–	7.0 (5.9)	19.1 (10.6)	–
25 mg (n=6)	0.087 (0.014)	0.107 (0.022)	–	26.4 (38.2)	–	6.2 (2.0)	19.1 (3.7)	–
50 mg (n=8)	0.075 (0.020)	0.111 (0.029)	–	51.0 (36.6)	–	8.3 (2.8)	18.6 (6.9)	–
100 mg (n=8)	0.092 (0.019)	0.106 (0.014)	–	17.0 (16.3)	–	5.3 (0.9)	24.4 (6.3)	–
200 mg (n=8) (fasting)	0.104 (0.028)	0.130 (0.016)	–	32.6 (37.4)	–	9.9 (3.4)	31.2 (6.7)	–
200 mg (n=8) (fed)*		0.122 (0.013)		8.8 (11.8)		–	22.4 (8.5)
400 mg (n=8)	0.120 (0.032)	0.140 (0.035)	–	19.1 (20.8)	–	5.9 (2.5)	32.2 (12.0)	–
600 mg (n=8)	0.094 (0.026)	0.107 (0.015)	–	18.5 (19.8)	–	6.9 (2.6)	26.6 (6.1)	–
Placebo (n=14)	0.104 (0.033)	0.103 (0.024)	–	3.8 (28.7)	–	7.2 (2.9)	7.5 (3.7)	–
MAD study
100 mg (n=8)	0.123 (0.015)	0.130 (0.023)	0.133 (0.018)	6.0 (17.3)	8.5 (13.1)	5.0 (1.5)	17.7 (6.2)	19.5 (6.5)
200 mg (n=8)	0.183 (0.057)	0.231 (0.057)	0.191 (0.051)	35.4 (46.0)	7.3 (14.7)	3.6 (1.8)	10.7 (2.9)	22.7 (7.0)
400 mg (n=8)	0.158 (0.044)	0.156 (0.034)	0.162 (0.024)	1.5 (17.6)	6.6 (17.8)	4.6 (1.3)	24.1 (5.7)	26.9 (7.7)
600 mg (n=8)	0.156 (0.073)	0.160 (0.056)	0.166 (0.037)	9.5 (21.9)	22.3 (48.3)	3.9 (2.1)	17.4 (8.3)	21.5 (7.3)
800 mg (n=6)	0.105 (0.023)	0.108 (0.016)	0.135 (0.019)	5.1 (19.6)	32.1 (26.7)	4.3 (1.5)	18.0 (3.6)	32.5 (10.5)
Febuxostat 80 mg (n=8)	0.173 (0.060)	0.183 (0.061)	0.171 (0.054)	9.2 (34.6)	3.3 (31.8)	3.8 (2.2)	17.4 (11.2)	22.3 (7.6)
Placebo (n=10)	0.149 (0.043)	0.135 (0.036)	0.154 (0.035)	−8.2 (13.9)	5.9 (20.6)	4.1 (2.1)	5.1 (2.8)	4.4 (2.3)

Notes: All values are presented as mean (SD).

* Data of 200 mg dose group under fed condition.

Abbreviations: C_mean,24, 24-hour mean serum concentrations of hypoxanthine; CL_R, renal clearance of hypoxanthine; min, minutes; SAD, single ascending dose; MAD, multiple ascending dose; SD, standard deviation.

Table 4 Summary of pharmacokinetic parameters for LC350189 in the single ascending dose study

	Cmax (ng/mL)	Tmax (h)	AUClast (h·ng/mL)	AUCinf (h·ng/mL)	CL/F (L/h)	t1/2 (h)	Ae0–72h (mg)	CLR (L/h)	fe
10 mg (n=6)	313.3 (118.4)	2.8 (2.5–4.0)	1,680.5 (620.5)	1,770.0 (620.6)	6.4 (2.8)	5.1 (1.6)	2.49 (0.79)	1.5 (0.5)	0.249 (0.079)
25 mg (n=6)	978.0 (126.2)	2.3 (2.0–4.0)	5,008.3 (664.9)	5,186.4 (678.9)	4.9 (0.6)	8.1 (3.8)	9.23 (3.78)	1.8 (0.5)	0.369 (0.151)
50 mg (n=8)	1,441.3 (287.3)	3.0 (2.5–4.0)	6,977.4 (1,674.4)	7,121.3 (1,612.9)	7.3 (1.5)	7.1 (2.9)	9.84 (5.02)	1.4 (0.7)	0.197 (0.100)
100 mg (n=8)	3,525.0 (321.8)	3.5 (2.0–5.0)	19,435.8 (4,432.1)	19,574.5 (4,413.5)	5.3 (1.2)	6.6 (1.0)	20.18 (9.79)	1.0 (0.5)	0.202 (0.098)
200 mg (n=8) (fasting)	8,767.5 (2,611.8)	2.7 (1.0–6.0)	43,864.5 (13,322.2)	44,304.3 (13,234.5)	4.8 (1.3)	13.3 (18.1)	54.83 (13.30)	1.3 (0.2)	0.274 (0.066)
200 mg (n=8) (fed)	5,400.0 (1,352.6)	5.0 (3.0–6.0)	43,702.1 (18,895.1)	44,340.0 (18,642.7)	5.0 (1.4)	15.0 (19.7)	51.02 (18.74)	1.2 (0.3)	0.255 (0.094)
400 mg (n=8)	14,731.0 (3,676.6)	3.0 (1.5–4.0)	91,495.5 (18,918.8)	92,006.2 (18,705.8)	4.5 (1.0)	13.1 (9.3)	90.55 (29.62)	1.1 (0.5)	0.226 (0.074)
600 mg (n=8)	18,207.9 (1,881.5)	2.5 (1.5–3.5)	98,839.8 (11,379.3)	99,784.2 (12,253.5)	6.1 (0.7)	11.9 (8.0)	168.03 (130.81)	1.8 (1.6)	0.280 (0.218)

Note: All values are presented as mean ± SD, except for T_max for which the median (range) is presented.

Abbreviations: C_max, maximum plasma drug concentration; T_max, time to reach peak plasma drug concentrations; AUC_last, area under the plasma concentration–time curve (AUC) from 0 h to 72 h; h, hours; AUC_inf, AUC from time zero to infinity; CL/F, apparent total clearance of the drug from plasma after oral administration; t_1/2, elimination half-life; Ae_0–72h, total amount excreted unchanged in the urine from 0 h to 72 h; CL_R, renal clearance, calculated as CL_R = A_e/AUC; f_e, fraction of unchanged drug excreted in urine calculated as A_e/Dose; SD, standard deviation.

Table 5 Summary of plasma pharmacokinetic parameters for LC350189 in the multiple ascending dose study

	Cmax,ss (ng/mL)	Tmax,ss (h)	AUCtau,ss (h·ng/mL)	CL/F (L/h)	t1/2 (h)	Accumulation ratio	Ae tau (mg)	CLR	fe
100 mg (n=8)	4,625.8 (932.9)	2.5 (1.0–3.0)	20,692.9 (5,267.8)	5.1 (1.5)	8.6 (7.5)	1.1 (0.1)	23.51 (7.89)	1.2 (0.4)	0.235 (0.079)
200 mg (n=8)	9,393.7 (2,896.2)	2.5 (1.5–5.0)	47,538.8 (10,643.0)	4.4 (0.9)	11.6 (8.9)	1.2 (0.2)	50.55 (20.75)	1.1 (0.4)	0.253 (0.104)
400 mg (n=8)	13,623.2 (3,574.7)	2.5 (1.5–5.0)	71,127.1 (27,953.1)	6.2 (1.8)	12.6 (6.7)	1.1 (0.3)	78.02 (48.65)	1.0 (0.2)	0.195 (0.122)
600 mg (n=8)	17,273.2 (4,474.6)	3.5 (2.5–4.0)	101,966.3 (41,006.2)	6.7 (2.3)	11.7 (6.4)	1.1 (0.3)	97.77 (49.94)	1.1 (0.8)	0.163 (0.083)
800 mg (n=6)	26,590.2 (6,479.8)	4.0 (2.5–5.0)	180,136.8 (52,519.4)	4.7 (1.2)	13.8 (9.7)	1.3 (0.2)	148.06 (57.56)	0.9 (0.4)	0.185 (0.072)

Note: All values are presented as mean ± SD, except for T_max for which median (range) is presented.

Abbreviations: C_max,ss, maximum plasma drug concentration at steady state; T_max,ss, time to reach peak plasma drug concentrations at steady state; h, hours; AUC_tau,ss, area under the plasma concentration–time curve (AUC) from 0 h to 24 h at steady state; CL/F, apparent total clearance of the drug from plasma after oral administration; t_1/2, elimination half-life; A_{e tau}, total amount excreted in the urine during dosing interval tau; CL_R, renal clearance, calculated as CL_R = A_{e tau}/AUC_tau; f_e, fraction of unchanged drug excreted in urine calculated as A_e/Dose.

Figure 5 Mean plasma concentration–time curves following single oral administration of LC350189.

Notes: (A) Comparison among dose groups (under fasting status). The inset shows the concentration–time curves up to 24-h post dose for LC350189. (B) Comparison between under fasting and fed status.
Abbreviation: h, hours.

Figure 6 Mean plasma concentration–time curves following once-daily oral administration of LC350189 for 7 days.

Abbreviation: h, hours.

Figure 7 The relationship between the percentage decrease in 24-hour mean concentration (C_mean,24) of serum uric acid and the area under the plasma concentration–time curve of LC350189 (AUC_tau,ss) on day 7 following multiple-dose administration with LC350189.

Note: The line represents the best-fit line based on the E_max model, and each symbol represents the observed data.
Abbreviation: hr, hours.

Table 6 Summary of adverse events

	Adverse event	Drug-related* adverse event
SAD study (n=67)
10 mg (n=6)	2 (2)	1 (1)	Back pain
25 mg (n=6)	2 (1)	2 (1)	Nasal congestion, sneezing
50 mg (n=8)	2 (1)	–
100 mg (n=8)	2 (1)	2 (1)	Flushing, headache
200 mg (n=8)	6 (3)	6 (3)	Diarrhea, feeling hot, headache, nasal congestion, rhinorrhea, throat irritation
400 mg (n=8)	–	–
600 mg (n=8)	1 (1)	–
Placebo (n=14)	2 (2)	2 (2)	Musculoskeletal chest pain, oropharyngeal pain
Subtotal	17 (11)	13 (8)
MAD study (n=58)
100 mg (n=8)	2 (1)	1 (1)	Hematochezia
200 mg (n=8)	–	–
400 mg (n=8)	2 (2)	–
600 mg (n=8)	6 (5)	5 (4)	Diarrhea, flatulence, lip ulceration, nausea, fatigue
800 mg (n=6)	1 (1)	–
Febuxostat 80 mg (n=8)	5 (3)	5 (3)	Lip blister, lip swelling, loose stool, headache, dermatitis acneiform
Placebo (n=10)	4 (3)	2 (1)	Diarrhea, dizziness
Subtotal	20 (15)	13 (9)

Notes: All values are presented as number of adverse events (number of subjects with adverse events).

* The adverse event was counted as drug related when its causality assessment was certain, probable, or possible.

Abbreviations: SAD, single ascending dose; MAD, multiple ascending dose.

Table S1 Sampling procedures for PK and PD analysis and sample handling process

		Dose groups	Time points for blood sample collection	Time interval for urine sample collection
PK	SAD study	10 mg, 25 mg 50 mg, 100 mg, 400 mg, 600 mg 200 mg (food interaction study)	0 h (predose), 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, 72 h 0 h (predose), 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, 72 h (day 1) 0 h (predose), 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, 72 h (days 1 and 8)	Day 1: 0–6 h, 6–12 h, 12–24 h Day 1: 0–6 h, 6–12 h, 12–24 h, 24–48 h, 48–72 h Day 1: 0–6 h, 6–12 h, 12–24 h Day 1: 0–6 h, 6–12 h, 12–24 h, 24–48 h, 48–72 h Day 8: 0–6 h, 6–12 h, 12–24 h, 24–48 h, 48–72 h
	MAD study	100 mg, 200 mg, 400 mg, 600 mg, 800 mg	Day 1: 0 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h Days 3–6: 0 h (predose) Day 7: 0 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h 5 mL of blood was drawn and collected into a sodium heparinized tube. The blood samples were centrifuged at 1,500× g for 10 minutes at 4°C within 20 minutes after collection. After centrifugation, 1.5 mL of a plasma sample were added to 1.5 mL of 5% (v/v) formic acid in double distilled water and gently mixed. Two aliquots of 1 mL, 2 mL in total, were transferred into two Eppendorf tubes	Day 1: 0–6 h, 6–12 h, 12–24 h Day 1: 0–6 h, 6–12 h, 12–24 h Day 7: 0–6 h, 6–12 h, 12–24 h, 24–48 h, 48–72 h 5 mL of a urine sample was added into tubes containing 5 mL of 5% (v/v) formic acid in double distilled water and was gently mixed. Two aliquots of 5 mL of urine each were transferred into polypropylene tubes
PD	SAD study	10 mg, 25 mg, 50 mg, 100 mg, 400 mg, 600 mg 200 mg (food interaction study)	Day 1: 0 h, 6 h, 12 h, 24 h (day 1, predose) Day 1: 6 h, 12 h, 24 h Day 1: 0 h, 6 h, 12 h, 24 h (day 1, predose) Day 1: 6 h, 12 h, 24 h Day 8: 0 h (predose), 6 h, 12 h, 24 h	Day 1: 0–6 h, 6–12 h, 12–24 h Day 1: 0–6 h, 6–12 h, 12–24 h, 24–48 h, 48–72 h Day 1: 0–6 h, 6–12 h, 12–24 h Day 1: 0–6 h, 6–12 h, 12–24 h, 24–48 h, 48–72 h Day 8: 0–6 h, 6–12 h, 12–24 h, 24–48 h, 48–72 h
	MAD study	100 mg, 200 mg, 400 mg, 600 mg, 800 mg	Day 1: 0 h, 6 h, 12 h, 24 h (day 1, predose) Day 1: 6 h, 12 h, 24 h Days 3–6: 0 h (predose) Day 7: 0 h (predose), 6 h, 12 h, 24 h Within 20 minutes of the collection, it was centrifuged at 1,500× g, 4°C, and two aliquots of 1 mL of serum, 2 mL in total, were transferred into two Eppendorf tubes	Day 1: 0–6 h, 6–12 h, 12–24 h Day 1: 0–6 h, 6–12 h, 12–24 h Day 7: 0–6 h, 6–12 h, 12–24 h, 24–48 h, 48–72 h Two aliquots of 5 mL of urine for the PD analysis were transferred into polypropylene tubes

Note: All of the PK and PD aliquots were stored at −70°C until analysis.

Abbreviations: PK, pharmacokinetic; PD, pharmacodynamic; SAD, single ascending dose; h, hours; MAD, multiple ascending dose.

Table S2 Amount of uric acid, xanthine, and hypoxanthine excreted in urine

Ae (mg)	Uric acid			Xanthine			Hypoxanthine
	Baseline	Day 1 (Day 8*)	Day 7	Baseline	Day 1 (Day 8*)	Day 7	Baseline	Day 1 (Day 8*)	Day 7
SAD study
10 mg (n=6)	592.1 (119.3)	498.3 (103.7)	–	9.4 (2.8)	68.8 (9.0)	–	9.0 (4.4)	24.6 (10.1)	–
25 mg (n=6)	548.8 (111.5)	536.7 (43.2)	–	6.8 (0.9)	86.1 (9.7)	–	7.5 (1.8)	28.7 (3.3)	–
50 mg (n=8)	611.6 (75.9)	466.3 (47.8)	–	8.2 (1.4)	106.5 (14.7)	–	8.5 (1.6)	27.7 (6.2)	–
100 mg (n=8)	522.1 (112.1)	436.3 (52.4)	–	6.4 (2.2)	134.1 (28.8)	–	7.0 (2.0)	36.6 (8.6)	–
200 mg (n=8) (fasting)	710.1 (91.3)	552.8 (108.6)	–	8.0 (1.8)	174.0 (28.6)	–	14.0 (4.1)	58.7 (17.3)	–
200 mg (n=8) (fed)*	–	574.3 (64.9)		–	148.3 (41.6)		–	38.3 (12.4)
400 mg (n=8)	716.5 (204.1)	563.8 (92.7)	–	8.6 (2.5)	247.9 (52.1)	–	9.5 (2.4)	67.0 (39.9)	–
600 mg (n=8)	563.3 (83.6)	511. 9 (88.8)	–	7.2 (2.0)	197.6 (45.6)	–	8.6 (2.5)	40.5 (6.8)	–
Placebo (n=14)	652.5 (163.0)	653.8 (153.3)	–	9.3 (2.0)	7.9 (2.1)	–	10.3 (3.7)	10.6 (4.3)	–
MAD study
100 mg (n=8)	526.5 (109.0)	410.8 (75.3)	187.7 (45.8)	7.7 (1.7)	124.0 (28.6)	129.0 (27.3)	8.7 (1.8)	31.8 (7.5)	36.5 (9.6)
200 mg (n=8)	529.7 (93.1)	421.4 (62.9)	124.2 (15.1)	8.1 (2.4)	189.0 (36.6)	258.8 (41.6)	8.4 (1.7)	34.2 (6.0)	59.6 (15.3)
400 mg (n=8)	536.9 (106.5)	490.0 (48.3)	99.8 (20.1)	7.6 (1.9)	175.5 (17.0)	247.6 (45.2)	9.9 (1.9)	52.9 (11.1)	61.8 (15.5)
600 mg (n=8)	439.5 (154.6)	570.3 (282.2)	79.7 (26.2)	8.9 (10.5)	167.1 (37.3)	242.4 (36.2)	8.1 (6.2)	351. (8.2)	49.1 (13.5)
800 mg (n=6)	510.7 (204.0)	652.9 (134.0)	60.7 (8.6)	5.0 (1.8)	182.3 (36.1)	318.6 (86.2)	6.2 (1.6)	27.5 (3.8)	61.7 (15.5)
Febuxostat 80 mg (n=8)	472.6 (95.8)	417.8 (59.9)	182.6 (53.4)	6.3 (2.0)	140.0 (29.8)	193.0 (25.6)	8.1 (2.9)	40.2 (18.1)	54.3 (25.8)
Placebo (n=10)	546.8 (82.8)	602.5 (100.8)	582.9 (108.9)	6.7 (1.6)	6.9 (1.6)	6.9 (1.4)	8.1 (2.8)	8.9 (3.0)	8.7 (2.6)

Notes: All values are presented as mean (SD).

* Data of 200 mg dose group under fed condition.

Abbreviations: A_e, cumulative amount excreted in the urine for 24 h; SAD, single ascending dose; MAD, multiple ascending dose; SD, standard deviation.