A phase I pharmacokinetic study of ursolic acid nanoliposomes in healthy volunteers and patients with advanced solid tumors

Figures & data

Table 1 Summary of healthy volunteer and patient characteristics

	Single-dose pharmacokinetics			Multiple-dose pharmacokinetics
	37 mg/m^2 N = 8	74 mg/m^2 N = 8	98 mg/m^2 N = 8	74 mg/m^2 N = 8
Sex
Male	8	2	7	6
Female	0	6	1	2
Age (years)
Mean, range	23 (21–27)	22 (20–23)	22 (20–27)	49 (33–68)
Height (cm)
Mean, range	168 (156–178)	165 (155–177)	173 (168–178)	170 (154–178)
Weight (kg)
Mean, range	63 (55–72)	57 (50–75)	69 (54–84)	70 (56–96)
Body surface area (m^2)
Mean, range	1.71 (1.56–1.86)	1.63 (1.47–1.92)	1.79 (1.61–1.98)	1.82 (1.53–2.15)
BMI (kg·m^−2)
Mean, range	22.3 (19.0–23.8)	20.9 (19.5–23.9)	22.2 (19.1–23.9)	24.2 (23.6–30.3)
ECOG status at entry
0–1	–	–	–	8
Tumor types
Non-Hodgkin’s lymphoma	–	–	–	4
Hodgkin’s lymphoma	–	–	–	1
Hepatoma	–	–	–	2
Gastric cancer	–	–	–	1

Note: Data are expressed as mean (Range).

Abbreviations: BMI, body mass index; ECOG, Eastern Cooperative Oncology Group.

Table 2 Main pharmacokinetic parameters after single intravenous doses of ursolic acid nanoliposomes in healthy volunteers

Parameters	Dose level (mg/m^2)
	37 N = 8	74 N = 8	98 N = 8
t1/2 (hour)	4.59 (2.44)	4.46 (1.41)	3.90 (2.08)
Vd (L/m^2)	58.7 (33.0)	64.3 (17.9)	55.4 (28.1)
CL (L/hour/m^2)	8.67 (1.07)	10.20 (1.46)	9.94 (1.13)
AUC0–16 h (ng·hour/mL)	4203 (588)	7175 (999)	9696 (1134)
AUC0–∞ (ng·hour/mL)	4329 (556)	7418 (1057)	9971 (1144)
MRT0–16 h (hour)	3.69 (0.36)	3.93 (0.37)	3.84 (0.34)
MRT0–∞ (hour)	4.29 (0.90)	4.56 (0.88)	4.41 (0.95)
Cmax (ng/mL)	1835 (438)	2865 (868)	3457 (856)
Tmax (h)	4.03 (0.04)	4.02 (0.04)	4.00 (0)

Note: Values are expressed as mean (standard deviation).

Abbreviations: t_1/2, half-life; Vd, volume of distribution; CL, clearance; AUC, area under the concentration–time curve; MRT, mean residence time; C_max, maximum plasma concentration; T_max, time to maximum plasma concentration.

Figure 1 Mean logarithmic concentration versus time plot after receiving 37 mg/m² (♦, n = 8), 74 mg/m² (■, n = 8), or 98 mg/m² (▲, n = 8) of ursolic acid nanoliposomes intravenously.

Table 3 Main pharmacokinetic parameters at day 1 and day 14 after multiple doses of ursolic acid nanoliposomes in patients with advanced solid tumors

Parameters	Day 1	Day 14	P
t1/2 (hour)	4.58 (2.04)	4.00 (1.27)	0.563
Vd (L/m^2)	88.6 (31.8)	89.9 (28.1)	0.947
CL (L/hour/m^2)	14.40 (3.94)	15.80 (3.05)	0.383
AUC0–16 h (ng·hour/mL)	5172 (1136)	4705 (873)	0.362
AUC0–∞ (ng·hour/mL)	5498 (1525)	4834 (933)	0.291
MRT0–16 h (hour)	3.34 (0.55)	3.30 (0.31)	0.809
MRT0–∞ (hour)	4.31 (1.89)	3.78 (0.70)	0.469
Cmax (ng/mL)	1589 (635)	1211 (204)	0.109
Tmax (h)	3.00 (1.41)	3.63 (1.06)	0.279

Note: Values are expressed as mean (standard deviation).

Abbreviations: t_1/2, half-life; Vd, volume of distribution; CL, clearance; AUC, area under the concentration–time curve; MRT, mean residence time; C_max, maximum plasma concentration; T_max, time to maximum plasma concentration.

Figure 2 Mean logarithmic concentration versus time plot after receiving 74 mg/m² ursolic acid nanoliposomes for the 14-day continuous intravenous infusion (n = 8).

Table 4 Numbers of subjects with ursolic acid nanoliposome-associated adverse events

Toxicity (CTC)	Single-dose groups						Multiple-dose group
	74 mg/m^2 N = 8			98 mg/m^2 N = 8			74 mg/m^2 N = 8
	Grade 1	Grade 2	Grade 3	Grade 1	Grade 2	Grade 3	Grade 1	Grade 2	Grade 3
Gastrointestinal disorders
Nausea	2	0	0	0	0	0	0	0	0
Diarrhea	1	0	1	0	0	0	0	0	0
Abdominal distention	1	1	0	0	0	0	1	0	0
Constitutional
Fever	1	0	0	0	0	0	0	0	0
Metabolic disorders
AST	0	0	1	0	0	0	0	0	0
ALT	0	0	1	0	0	0	0	0	0
GGT	1	0	0	1	0	0	0	0	0
TG				1	0	0	1	0	0
TBIL				1	0	0
Pain
Arthralgia	0	0	0	0	0	0	1	0	0
Skin
Pruritus	0	0	0	0	0	0	1	0	0

Abbreviations: ALT, alannine aminotransferase; AST, aspartate aminotransferase; GGT, γ-glutamyl transferase; TG, triglyceride; TBIL, total bilirubin.