Safety, tolerability, pharmacokinetics and pharmacodynamics of a novel farnesoid X receptor (FXR) agonist-TQA3526 in healthy Chinese volunteers: a double-blind, randomized, placebo-controlled, dose-escalation, food effect phase I study

Figures & data

Table 1. Demographics of the subject in this study.

Cohort	Single ascending dose				Food effect	Multiple ascending doses		Placebo (N = 14)
	1 mg (N = 2)	2 mg (N = 8)	5 mg (N = 8)	10 mg (N = 8)	10 mg (N = 16)	2 mg (N = 8)	0.2 mg + 0.5 mg + 1 mg (N = 8)
Age (years)	36.0 ± 14.14	38.6 ± 8.25	35.4 ± 8.94	33.0 ± 4.66	34.7 ± 6.58	36.5 ± 7.84	35.6 ± 7.05	37.1 ± 8.28
Gender
Male	1 (50.00)	4 (50.00)	4 (50.00)	4 (50.00)	8 (50.00)	4 (50.00)	4 (50.00)	7 (50.00)
Female	1 (50.00)	4 (50.00)	4 (50.00)	4 (50.00)	8 (50.00)	4 (50.00)	4 (50.00)	7 (50.00)
Height (cm)	159.05 ± 6.576	165.55 ± 7.260	163.70 ± 8.407	162.39 ± 7.685	162.11 ± 7.888	163.44 ± 9.562	163.60 ± 10.012	162.70 ± 7.925
Weight (kg)	55.40 ± 6.505	63.49 ± 5.518	62.31 ± 9.873	61.65 ± 9.879	63.14 ± 10.050	61.20 ± 4.711	64.31 ± 8.207	65.08 ± 8.979
BMI (kg/m^2)	21.5 ± 0.71	23.3 ± 2.55	23.3 ± 2.71	23.3 ± 3.20	23.9 ± 2.67	23.0 ± 1.60	24.1 ± 3.18	24.6 ± 1.65
Alanine aminotransferase (U/L)	12.25 ± 5.445	18.56 ± 9.913	17.69 ± 9.577	17.66 ± 8.710	18.95 ± 8.648	14.43 ± 5.213	15.19 ± 8.693	18.69 ± 7.440
Aspartate aminotransferase (U/L)	25.65 ± 2.899	21.25 ± 4.080	18.84 ± 4.760	19.58 ± 4.585	20.96 ± 4.332	16.65 ± 4.313	20.13 ± 5.897	20.08 ± 3.950
Alkaline phosphatase (U/L)	50.10 ± 3.111	78.48 ± 18.981	70.91 ± 21.073	73.03 ± 11.949	68.54 ± 17.465	61.79 ± 24.903	54.33 ± 10.581	60.90 ± 21.287
Cholesterol (mmol/L)	4.120 ± 0.1838	4.936 ± 0.9839	4.538 ± 0.5628	4.353 ± 0.5093	4.388 ± 0.4564	4.144 ± 0.7260	3.844 ± 0.3836	4.725 ± 0.8766
Bile acid (umol/L)	7.40 ± 2.121	3.20 ± 1.869	3.35 ± 2.766	4.60 ± 2.210	3.95 ± 3.119	3.21 ± 2.677	3.79 ± 3.030	3.58 ± 1.837
Glucose (mmol/L)	5.300 ± 0.1697	4.621 ± 0.2469	4.840 ± 0.3153	4.706 ± 0.4109	4.652 ± 0.4051	4.609 ± 0.4303	5.173 ± 0.2691	4.784 ± 0.3458

Data are mean ± SD or n (%). BMI: body mass index.

Table 2. Adverse events incidence after administration of TQA3526 by dose cohort (n = 74).

Cohort	Single ascending dose					Food effect				Multiple doses
	1 mg (N = 2)	2 mg (N = 8)	5 mg (N = 8)	10 mg (N = 8)	Placebo (N = 6)	10 mg Fasted (N = 16)	10 mg Fed (N = 16)	Placebo Fasted (N = 2)	Placebo Fed (N = 2)	2 mg (N = 8)	0.2 mg + 0.5 mg + 1 mg (N = 8)	Placebo (N = 8)
AE	0	4 (50.00)	5 (62.50)	7 (87.50)	1 (16.67)	13 (81.25)	16 (100)	1 (50.00)	2 (100)	8 (100)	8 (100)	5 (62.50)
ADR	0	4 (50.00)	5 (62.50)	7 (87.50)	1 (16.67)	13 (81.25)	15 (93.75)	1 (50.00)	2 (100)	8 (100)	8 (100)	4 (50.00)
AE (grade ≥3)^a	0	1 (12.50)	1 (12.50)	0	0	2 (12.50)	9 (56.25)	0	1 (50.00)	7 (87.50)	5 (62.50)	0
ADR (grade ≥3)	0	1 (12.50)	1 (12.50)	0	0	2 (12.50)	9 (56.25)	0	1 (50.00)	7 (87.50)	5 (62.50)	0
SAE	0	0	0	0	0	0	0	0	0	0	0	0
Death	0	0	0	0	0	0	0	0	0	0	0	0
ADR occurring in at least two subjects
Hypocalcaemia	0	2 (25.00)	0	0	0	0	0	0	0	0	0	0
White blood cell decrease	0	1 (12.50)	2 (25.00)	1 (12.50)	0	2 (12.50)	1 (6.25)	0	0	1 (12.50)	2 (25.00)	0
Neutrophil count decrease	0	1 (12.50)	3 (37.50)	2 (25.00)	0	3 (18.75)	3 (18.75)	0	1 (50.00)	1 (12.50)	2 (25.00)	0
Alanine aminotransferase increase	0	0	0	1 (12.50)	0	2 (12.50)	2 (12.50)	0	0	4 (50.00)	3 (37.50)	1 (12.50)
Aspartate aminotransferase increase	0	0	0	1 (12.50)	0	2 (12.50)	4 (25.00)	0	0	4 (50.00)	5 (62.50)	0
Thyroid-stimulating hormone decrease	0	0	1 (12.50)	1 (12.50)	0	1 (6.25)	0	0	0	0	0	0
Bile acid increase	0	0	0	0	0	0	1 (6.25)	0	0	1 (12.50)	0	0
Arthralgia	0	0	0	1 (12.50)	0	1 (6.25)	0	0	0	0	0	0
Pruritus	0	1 (12.50)	2 (25.00)	7 (87.50)	1 (16.67)	13 (81.25)	15 (93.75)	1 (50.00)	1 (50.00)	8 (100)	8 (100)	1 (12.50)
Vomiting	0	0	0	0	0	0	0	0	0	2 (25.00)	0	0
Diarrhea	0	0	0	0	0	0	1 (6.25)	0	0	1 (12.50)	0	1 (12.50)
Supraventricular arrhythmia	0	0	0	1 (12.50)	0	1 (6.25)	1 (6.25)	0	0	1 (12.50)	0	0

^aThe Common Terminology Criteria for Adverse Events (CTCAE 5.0) was used to grade adverse events (grades 1–5). Data are n (%). AE: adverse event; ADR: adverse drug reaction; N: number of subjects analysed.

Figure 1. Mean (±SD) TQA3526 concentrations (ng/mL) versus time profiles (A) in the single ascending dose study and (B) the multiple dose study.

Table 3. Plasma pharmacokinetic parameters in the single ascending dose study.

Cohort	t1/2	Tmax	Cmax	AUC0–72 h	AUC0–∞	Vz/F	CL/F
	(h)	(h)	(ng/mL)	(h·ng/mL)	(h·ng/mL)	(L)	(L/h)
Single ascending dose study
1 mg (n = 8)	8.92 ± 0.57	2.50 (2.00–3.00)	10.92 ± 3.50	158.08 ± 40.90	158.93 ± 41.44	83.12 ± 16.46	6.51 ± 1.70
2 mg (n = 8)	12.90 ± 2.66	4.00 (2.00–8.00)	17.38 ± 2.83	297.92 ± 60.74	305.27 ± 63.67	124.02 ± 24.06	6.81 ± 1.44
5 mg (n = 8)	14.54 ± 2.40	4.00 (3.00–6.00)	48.74 ± 11.13	841.48 ± 227.83	871.24 ± 240.94	125.35 ± 27.57	6.04 ± 1.30
10 mg (n = 8)	16.69 ± 6.36	4.00 (3.00–6.00)	94.62 ± 30.01	1704.04 ± 566.46	1817.85 ± 681.73	134.45 ± 24.38	6.07 ± 1.30
Food effect study (10 mg)
Fasted (n = 14)	16.23 ± 5.55	4.00 (3.00–8.00)	97.70 ± 27.50	1889.28 ± 700.71	2014.64 ± 821.70	122.90 ± 29.06	5.74 ± 2.14
Fed (n = 16)	16.78 ± 3.56	5.00 (2.00–8.00)	118.34 ± 29.24	2384.38 ± 766.55	2543.96 ± 887.63	100.54 ± 20.36	4.40 ± 1.52

Data are expressed as mean ± SD unless otherwise specified. T_max is expressed as median (range).

Table 4. Plasma pharmacokinetic parameters in the multiple dose study.

Treatment	Day 1			Day 7
	Tmax (h)	Cmax (ng/mL)	AUC0–24 h (h·ng/mL)	t1/2,ss (h)	Tmax,ss (h)	Cmax,ss (ng/mL)	Cmin,ss (ng/mL)	AUCtau,ss (h × ng/mL)	AUC0–∞,ss (h × ng/mL)	AUC0–72,ss (h × ng/mL)	CL/Fss (L/h)	Vz/Fss (L)	RAUC	DF (%)
2 mg QD (n = 8)	3.00 (3.00 − 6.00)	17.61 ± 4.30	236.26 ± 53.75	14.78 ± 3.59	4.00 (3.00–6.00)	39.74 ± 18.06	9.88 ± 6.08	553.92 ± 271.22	829.20 ± 468.64	790.70 ± 434.32	4.58 ± 2.53	88.45 ± 30.24	2.64 ± 1.22	136.48 ± 21.00
Treatment	Day 20				Day 30
	Tmax,ss (h)	Cmax,ss (ng/mL)	Cmin,ss (ng/mL)	AUCtau,ss (h·× ng/mL)	t1/2,ss (h)	Tmax,ss (h)	Cmax,ss (ng/mL)	Cmin,ss (ng/mL)	AUCtau,ss (h × ng/mL)	AUC0–∞,ss (h × ng/mL)	AUC0–72,ss (h × ng/mL)	CL/Fss (L/h)	Vz/Fss (L)	–	DF (%)
0.2 + 0.5 + 1 mg QD (n = 8)	3.50 (1.50–8.00)	5.32 ± 0.90	1.24 ± 0.18	76.08 ± 14.80	16.80 ± 4.69	4.00 (2.00–6.00)	17.85 ± 4.39	5.74 ± 2.22	288.45 ± 88.14	476.52 ± 207.77	440.48 ± 172.88	3.86 ± 1.61	86.06 ± 13.07	–	105.10 ± 18.80

Figure 2. Pharmacokinetic/pharmacodynamic profiles of FGF-19 for the single ascending dose study.

Figure 3. Mean (±SD) ALP (U/L), cholesterol (mmol/L), and bile acid (umol/L) concentrations versus time profiles in the single ascending dose study (A–C) and the multiple dose study (D–F).

Figure 4. Mean (±SD) FGF-19 (pg/mL) and C4 (ng/mL) concentrations versus time profiles in the multiple dose study (A) FGF-19 for 2 mg cohort, (B) FGF-19 for 0.2 + 0.5 + 1 mg, (C) C4 for 2 mg cohort, and (D) C4 for 0.2 + 0.5 + 1 mg.

Data availability statement

Data are not available due to ethical restrictions.