Download Report

1
A phase I trial to evaluate the multiple-dose tolerability safety
2
and
3
patientssubjects with advanced solid tumors
antitumor
activity
of
ursolic
acid
liposomes
in
4
5
Zhengzi Qian†, Xianhuo Wang†, Zheng Song, Huilai Zhang, Shiyong Zhou, Jing Zhao
6
and Huaqing Wang*
7
8
E- mail address:
9
Zhengzi Qian
[email protected]
10
Xianhuo Wang
[email protected]
11
Zheng Song
[email protected]
12
Huilai Zhang
[email protected]
13
Shiyong Zhou
[email protected]
14
Jing Zhao
[email protected]
15
Huaqing Wang
[email protected]
16
17
†
The authors contributed equally to this work.
18
19
Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, Tianjin
20
Medical University Cancer Institute and Hospital, National Clinical Research Center
21
of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tiyuanbei, Huanhuxi
22
Road, Hexi District, Tianjin 300060, China.
1
23
24
*
E-mail address for correspondence: [email protected].
25
2
26
Abstract
27
Background: Ursolic acid liposome (UAL), a new antitumor drug, has potential
28
therapeutic value. However, limited clinical data exists regarding multiple-dose
29
tolerabilitysafety, antitumor activity, and the recommended dose (RD) of UAL in a
30
phase II trial of patientssubjects with advanced solid tumors.
31
32
Methods: All patientssubjects were intravenously administered UAL for 14
33
consecutive days of a 21-day treatment cycle. Twenty-one patientssubjects were
34
enrolled in 1 of 3 sequential cohorts (56, 74, and 98 mg/m2 ) to evaluate multiple-dose
35
tolerability and efficacy. Eight additional patientssubjects were treated with UAL (74
36
mg/m2 ) to evaluate multiple-dose pharmacokinetics.
37
38
Results: Treatment-related adverse events included elevated aspartate transaminase,
39
alanine transaminase, gamma- glutamyl transpeptidase, and triglycerides levels;
40
abdominal distention; pruritus; arthralgia; pyrexia; hypokalemia; and microscopic
41
hematuria and proteinuria. However, no ≥grade 3 adverse events (NCI-CTC) were
42
observed. Sixty percent patientssubjects achieved stable disease after 2 treatment
43
cycles. Multiple-dose pharmacokinetic analysis revealed no significant differences in
44
the elimination half- life, maximum plasma concentration, area under the plasma
45
concentration time curve (AUC 0→t ), and AUC0→∞ values between days 1–14
46
(P > 0.05), suggesting UAL does not accumulate in the body.
47
3
48
Conclusions: This trial demonstrates that UAL was tolerable, had manageable
49
toxicity, could potentially improve patient remission rates, and did not accumulate in
50
the body. A large phase II study is recommended to confirm these results (i.e. RD of
51
98 mg/m2 ).
52
53
Trial registration: Chinese Clinical Trial Registry: ChiCTR-ONC-12002385.
54
55
Keywords: Ursolic acid liposome; Phase I; Multiple-dose administration; Tolerability;
56
Pharmacokinetics; Antitumor activity
57
58
59
60
61
62
63
64
65
66
67
68
69
70
4
71
Introduction
72
Ursolic acid (UA) is a natural hydroxy pentacyclic triterpene compound (Figure 1)
73
isolated from Chinese herbs including Eriobotrya japonica, Rosmarinus officinalis,
74
and Glechoma hederaceae [1, 2]. Previous studies have indicated that UA can induce
75
apoptosis [3-5] and cell differentiation [6, 7], inhibit invasion and metastasis [8], and
76
inhibit angiogenesis [9-11] in various tumors. UA treatment is also safe [12]. Thus,
77
UA is a potentially valuable compound. However, the poor solubility of UA in
78
hydrous solutions greatly limits its applications.
79
80
Liposomes have been utilized as a drug delivery system to overcome the poor
81
solubility of UA, increase the therapeutic efficiency, reduce the side-effects, and
82
enhance the bioavailability of drugs that have been broadly applied [13-15]. Currently,
83
ursolic acid liposomes (UALs) have been studied successfully and have been
84
approved by the State Food and Drug Administration (SFDA) of China to enter
85
clinical trials (NO. 2009L00634). We have previously published data regarding the
86
maximum tolerated dose, dose- limiting toxicity (DLT), and pharmacokinetics of UAL
87
in a single-dose administration study. The recommended doses in multiple-dose
88
administration trials of UAL are 56, 74, and 98 mg/m2 [16]. In actuality, multiple-dose
89
administration is usually adopted for most of drugs in clinic. Therefore, it is more
90
important to study the effects of UALs in a multiple-dose administration trial.
91
92
The primary objective of this study was to evaluate the tolerability of UAL treatment
5
93
and the recommended dose (RD) in a multiple-dose administration phase II trial
94
consisting of patientssubjects with advanced solid tumors. The second objective was
95
to perform a preliminary assessment of the antitumor activity of UALs.
96
97
Materials and Methods
98
We performed a phase I, open-label, single center trial in patientssubjects with
99
advanced solid tumors. The SFDA of China and the Hospital Medical Ethics
100
Committees approved the trial and it was conducted in accordance with the
101
Declaration of Helsinki and the applicable local regulatory requirements and laws. A
102
signed, written informed consent of the legal representatives and the consent of each
103
patient were obtained before any study procedure was performed. UALs were
104
supplied by Wuhan Li Yuanheng Medicine Technology Co. Ltd (Wuhan, China) as a
105
freeze-dried powder for infusion. Each glass vial contained 3 mg of active drug. It
106
was uniformly dispersed in 250 mL of 5% glucose solution before administration.
107
108
Patient eligibility
109
Eligible patientssubjects were aged 18–75 years with cytologically or histologically
110
confirmed advanced solid tumors; they either refused standard therapies or standard
111
effective therapies did not exist; they had an Eastern Cooperative Oncology Group
112
(ECOG) performance status (PS) of 0–2; a Karnofsky score ≥ 60%; a life
113
expectancy ≥ 3 months; practiced adequate contraception; had adequate hematological
114
function [white blood cell (WBC) ≥ 4.0 × 109 /L; absolute neutrophil count
6
115
(ANC) ≥ 2.0 × 109 /L; platelet count ≥ 100 × 109 /L; hemoglobin ≥ 100 g/L]; had
116
adequate hepatic and renal function [alanine transaminase (ALT), aspartate
117
transaminase (AST), and alkaline phosphatase (ALP) ≤ 2.5 the upper limit of normal
118
(ULN) (or 5 × ULN for hepatic cancer/metastatic hepatic cancer); total bilirubin
119
(TBIL) ≤ 1.5 × ULN; serum creatinine (CRE) levels of ≤ 1.5 × ULN; a creatinine
120
clearance rate of ≤ 1.5 × ULN; normal urea]; and had normal pulmonary function.
121
122
Study design and treatment
123
PatientsSubjects were assigned to 1 of 3 sequential dose cohorts of UAL: 56, 74, or
124
98 mg/m2 , administered via a 14-day consecutive, intravenous 4 h infusion, and given
125
a rest for 7-day per 21-day cycle. Each cohort consisted of at least 3 patientssubjects.
126
Once all enrolled patientssubjects had been monitored for 2 weeks and had no higher
127
than grade 3 non-hematological toxicity or grade 4 hematological toxicity, the next
128
dose was administered. The trial was terminated when ≥1/3 of the patientssubjects
129
experienced DLT, a severe adverse event (AE), or tumor progression. The DLT was
130
defined as grade 4 thrombocytopenia, grade 4 neutropenia lasting for ≥7 days, febrile
131
neutropenia, grade 4 anemia, or grade 3/4 non-hematological toxicity. Evaluated
132
patientssubjects were required to complete at least 1 cycle of treatment. After that, if
133
patientssubjects needed to continue treatment because they could not gain any benefit
134
from other treatments, additional cycles were administered until disease progression
135
or unacceptable toxicity occurred, or if the patient refused further treatment.
136
Additional patientssubjects were recruited in order to evaluate the pharmacokinetics
7
137
of UAL treatment. These patientssubjects were administered a dose of 74 mg/m2 of
138
UAL via a consecutive, 14-day, intravenous 4 h infusion.
139
140
Tolerability and toxicity
141
Tolerability and toxicity were evaluated in all patientssubjects treated with at least 1
142
cycle of UAL therapy. Vital signs including body temperature, respiration, pulsation,
143
and blood pressure were examined at screening and once a day thereafter.
144
Hematological parameters (red blood cell, WBC, hemoglobin, ANC, and platelet),
145
urine routines (urinary protein, glucose, erythrocyte, leukocyte and urine bilirubin),
146
and stool routines (fecal erythrocyte and fecal leukocyte) were tested, and an
147
electrocardiogram performed at screening and on the 14th day of the cycle. Blood
148
biochemistries including ALT, AST, ALP, gamma-glutamyl transpeptidase (GGT),
149
TBIL, direct-reacting bilirubin, total protein, GLU, lactate dehydrogenase, creatine
150
kinase, bun urea nitrogen, CRE, UA, cholesterol, triglyceride (TG), high-density
151
lipoprotein, low-density lipoprotein, K +, Na+, Ca2+ and Cl- were examined at screening
152
and then once a week thereafter. Fibrinogen (Fbg) and prothrombin time (PT) were
153
examined at screening and during the 3rd week. To further evaluate the immune
154
functions of patientssubjects after UAL administration, we measured CD4/CD8 and
155
natural killer (NK) cell activity in the circulation both at screening and on the 14th day.
156
AEs were evaluated according to the National Cancer Institute Common Terminology
157
Criteria for AEs (NCI-CTCAE) version 3.0.
158
8
159
160
Response evaluation
161
Serial randomly patientssubjects treated with at least 2 cycles were selected to
162
evaluate the therapeutic efficacy of UALs. The tumor response was examined by
163
using computerized tomography, magnetic resonance imaging, chest radiography, or
164
ultrasonography according to the response evaluation criteria in solid tumors
165
(RECIST) at the scheduled times (baseline and 2 cycles later) either until the tumor
166
progressed or until the final visit. Complete response (CR), partial response (PR),
167
stable disease (SD), and progressive disease (PD) were defined according to
168
RECIST.
169
170
Multiple-dose pharmacokinetics
171
Blood samples for pharmacokinetic analysis were collected into heparinized tubes on
172
the 1st and 14th days of the study, at various time points including 0, 0.5, 1, 2 and 4 h
173
during infusion, 5, 15 and 30 min, 1, 1.5, 2, 3, 4, 6, 8 and 12 h after the end of
174
infusion. Plasma was separated using centrifugation and then stored at –20 °C until
175
analysis.
176
177
UAL concentrations were measured using validated ultra-performance liquid
178
chromatography/tandem mass spectroscopy (UPLC/MS/MS) methods as described
179
previously [17]. In brief, chromatography was performed using a Waters Acquity
180
UPLCT M BEH C8 column (100 × 2.1 mm, 1.7 μm). The mobile phase consisted of
9
181
acetonitrile and 10 mM ammonium formate (9:1, v/v) at a flow rate of 0.2 mL/min.
182
The elution time was 3 m. Multiple-reaction monitoring was performed at m/z
183
455.1→455.0 and m/z 469.3→425.2 for UAL and glycyrrhetinic acid (internal
184
standard) respectively in negative ion mode with an electrospray ionization source.
185
Estimates of pharmacokinetic parameters for UAL were derived from individual
186
concentration-time data sets by non-compartmental analysis.
187
188
Statistical conside rations
189
Tolerability, toxicity, efficacy, and pharmacokinetic characteristics were explored and
190
analyzed in detail. Non-compartmental pharmacokinetic parameters were determined
191
from individual plasma concentration-time data using DAS version 2.1.1.
192
193
Results
194
Patient characte ristics
195
Twenty-one patientssubjects (7 men and 14 women), aged 19–68 years (median age:
196
54 years), were enrolled in the study, and their characteristics at baseline are listed in
197
Table 1. Twenty patientssubjects (95%) had an ECOG performance status of 0–1. All
198
patientssubjects were treated with surgery (43%), radiotherapy (52%), chemotherapy
199
(14%), and/or other therapies (67%). The study included 5 (24%) patientssubjects
200
with non-Hodgkin lymphoma, 5 (24%) patientssubjects with Hodgkin lymphoma, 1
201
(5%)
202
hepatomahepatocellular carcinoma, 1 (5%) patient with gallbladder carcinoma, 2 (9%)
patientssubjects
with
renal
carcinoma,
10
1
(5%)
patient
with
203
patientssubjects with breast cancer, 2 (9%) patientssubjects with lung cancer, and 4
204
(19%) patientssubjects with other cancer.
205
206
Tolerability and toxicity
207
Tolerability and toxicity were evaluated for all patientssubjects. The vital sign data
208
showed that all values fluctuated within the normal range at every time point among
209
the 3 cohorts (Figure 2). All hematological parameters, (Fbg, PT) and results of
210
electrocardiography and routine stool test were normal. Only 1 patient experienced
211
grade 1 microscopic hematuria, while 2 patientssubjects developed grade 1 proteinuria
212
after 2 cycles of treatment with UAL (74 mg/m2 ).
213
214
Immune function tests showed no significant differences in CD4/CD8 at screening
215
and on the 14th day (0.60 ± 0.31 and 0.82 ± 0.24, P > 0.05, 56 mg/m2 ; 0.82 ± 0.48 and
216
0.61 ± 0.24, P > 0.05, 74 mg/m2 ; 1.39 ± 0.96 and 1.23 ± 0.23, P > 0.05, 98 mg/m2 ).
217
Significant differences in the NK cells were also not observed (18.40 ± 7.66 and
218
22.60 ± 5.97, P > 0.05, 56 mg/m2 ; 17.52 ± 11.57 and 20.87 ± 8.58, P > 0.05,
219
74 mg/m2 ; 17.91 ± 10.02 and 18.40 ± 7.50, P > 0.05, 98 mg/m2 ). These results
220
suggested that the UAL did not affect patient immune function.
221
222
In addition, 3 (14%) patientssubjects treated with 56 mg/m2 UAL developed a
223
low-grade fever (grade 1) but then recovered after 2 h without any treatment (Table 2).
224
Three (14%) patientssubjects treated with 56, 74 and 98 mg/m2 UAL experienced
11
225
grade 2 GGT elevation. Two (10%) patientssubjects treated with 56 and 74 mg/m2
226
UAL experienced grade 1 abdominal distention. Finally, 1 (5%) patient had grade 2
227
ALT elevation. Other mild symptoms including AST and TG elevation, pruritus,
228
arthralgia, and hypokalemia were also observed. However, no National Cancer
229
Institute common toxicity criteria (NCI-CTC) ≥ grade 3 treatment-related AEs were
230
observed. The most frequent AEs included pyrexia, GGT elevation, and abdominal
231
distention. These results suggested that UAL was tolerable and safe among 3 dose
232
cohorts after administration via a consecutive 14-day intravenous 4 h infusion every
233
21 days. Therefore, a UAL dose of 98 mg/m2 was considered the RD for a phase II
234
trial.
235
236
Efficacy
237
As only 5 of 21 (23.8%) patientssubjects preferred to receive and finish at least 2
238
cycles of UAL treatment, the evaluation of preliminary antitumor efficacy was limited.
239
Three (60%) patientssubjects achieved stable disease. One of these patientssubjects
240
had advanced renal carcinoma and had no significant change in the lesion after 2
241
cycles of treatment with 56 mg/m2 UAL. Another patient that had advanced
242
hepatomahepatocellular carcinoma had no significant change in the lesion after 2
243
cycles of treatment with 74 mg/m2 UAL. Finally, the third patient had advanced lung
244
cancer in which the lesion shrunk from 9.6–7.5 cm after 2 cycles of treatment with 98
245
mg/m2 UAL.
246
12
247
Two additional patientssubjects, 1 with primary non-Hodgkin lymphoma and the other
248
with breast cancer, showed PD after 2 cycles treatment with 74 mg/m2 UAL. No CR
249
and PR were observed, which could be because the patientssubjects had advanced
250
stage tumors and did not benefit from other prior treatment schemes. Another possible
251
explanation is that the number of patientssubjects that could be evaluated was too
252
small. Regardless, UAL does have the potential to improve the patient remission rate.
253
A phase II study of a large number of patientssubjects is recommended to confirm this
254
finding.
255
256
Multiple-dose pharmacokinetics
257
Eight additional patientssubjects were enrolled in the trial in order to investigate the
258
pharmacokinetics of UAL therapy. The pharmacokinetic data (Table 3) following
259
multiple-dose administration showed that the values of the elimination half- life (t1/2 ),
260
maximum plasma concentration (C max ), area under the plasma concentration time
261
curve (AUC0→t ), and
262
1589 ± 635 ng/mL, 5172 ± 1136 ng·h/mL, and 5498 ± 1525 ng·h/mL respectively.
263
They were
264
4834 ± 933 ng·h/mL respectively during the 14th day. There were no significant
265
differences in the values of t1/2 , Cmax, AUC0→t , and AUC0→∞ (P > 0.05) between days
266
1–14, suggesting that the pharmacokinetics were unaltered with multiple-daily dosing
267
and that the UAL did not accumulate in the body. In addition, we found that there was
268
a close relationship between the values of C max or AUC and AEs. The value of C max or
4.00 ± 1.27
AUC0→∞ during the 1st day were 4.58 ± 2.04
h,
1211 ± 204
13
ng/mL,
4705 ± 873
ng·h/mL,
h,
and
269
AUC increased as the AEs (including hepatotoxicity and abdominal distension)
270
increased in seriousness.
271
272
Discussion
273
This study demonstrated that UAL treatment of patientssubjects with advanced solid
274
tumors via multiple-dose and consecutive 14-day intravenous infusion every 21 days
275
at doses of 56, 74, and 98 mg/m2 was safe. The results are consistent with preclinical
276
information [12]. In addition, multiple-dose pharmacokinetics showed that the value
277
of Cmax or AUC was associated with AEs. The value of Cmax or AUC was greater when
278
the risk of AEs occurring in patientssubjects was elevated. The reasons for this might
279
be the following: when the value of C max is elevated, hepatocytes would be exposed to
280
a high concentration of drug and would be stimulated to release serial enzymes
281
including AST, ALT, and GGT. If the value of AUC was high simultaneously, the time
282
of stimulation would be prolonged. Therefore, the risk of hepatotoxicity and
283
gastrointestinal toxicity would become elevated. These results suggested that the
284
manageable toxicity associated with UAL treatment could be further controlled via
285
kinetic monitoring.
286
287
UA has been widely reported to have antitumor activities in preclinical studies [3-11,
288
18-21]. However, the clinical antitumor effects of UA or UAL have not been reported
289
previously. In our study, the preliminary antitumor activity of UAL was evaluated for
290
the first time in 5 patientssubjects. Although no CR or PR occurred, SD was observed
14
291
in 3 (60%) patientssubjects with advanced solid tumors. Specifically, 1 lung cancer
292
patient showed significant improvement and the lesion decreased in size (range,
293
9.6–7.5 cm) after 2 cycles of treatment with a UAL dose of 98 mg/m2 . These results
294
indicate UAL can potentially improve patient remission.
295
296
The pharmacokinetic data of UA in animals showed that T1/2 was about 4.3 h [22]. In
297
this clinical trial, the mean T1/2 of UAL was 4.00-4.58 h, suggesting the T1/2 value was
298
low so that it could rapidly eliminate from blood. This phenomenon suggested that
299
UAL did not accumulate in the body, and that UAL must be infused repeatedly to
300
keep the plasma-drug concentration steady and further enhance its antitumor effect.
301
302
Conclusions
303
In summary, the multiple-dose administration of UAL was tolerable with manageable
304
toxicity. Further, the UAL did not accumulate in the body. We conclude that UAL has
305
the potential to improve the patient remission rates. The recommended dose of UAL
306
for a phase II clinical trial is 98 mg/m2 .
307
15
308
Abbreviations
309
UA: Ursolic acid; UAL: Ursolic acid liposome; RD: Recommended dose ; SFDA:
310
State Food and Drug Administration; MTD: Maximum tolerated dose; DLT:
311
Dose- limiting
312
Performance status; AEs: AEs; NCI-CTCAE: National Cancer Institute Common
313
Terminology Criteria for AEs; CT: Computerized tomography; MRI: Scan or
314
magnetic resonance imaging; CR: Complete response; PR: Partial response; SD:
315
Stable disease; PD: Progressive disease; UPLC/MS/MS: Ultra-performance liquid
316
chromatography/tandem mass spectroscopy; EIS: Electrospray ionization source; Fbg:
317
Fibrinogen; PT: Prothrombin time; t1/2: Elimination half- life; Cmax : Maximum plasma
318
concentration; AUC: Area under the plasma concentration time curve
toxicity; ECOG: Eastern Cooperative Oncology Group; PS:
319
320
Competing interests
321
The author(s) declare(s) that there is no conflict of interests regarding the publication
322
of this paper.
323
324
Author Contributions
325
The individual author contributions are following: ZQ contributed to the design and
326
implementation of the study protocol. XW contributed to data analysis and to writing
327
the manuscript. ZY contributed to data acquisition. ZS, HZ, SZ, LQ, JZ, and XM
328
participated in patient recruitment. PW and XH contributed to the design of the
329
protocol. HW designed the study and revised the manuscript. All the authors read and
16
330
approved the final manuscript.
331
332
Acknowledgme nts
333
The authors greatly appreciate financial support from the Tianjin Medical University
334
Cancer Hospital Doctoral Fund and the Tianjin Medical University Science Fund at
335
our institution. In addition, the authors thank Wuhan Li Yuanheng Medicine
336
Technology Co. Ltd (Wuhan, China) providing the UAL.
337
17
338
References
339
1. Liu
340
341
342
J: Oleanolic acid and
ursolic acid:
research pe rspectives.
J
Ethnopharmacol 2005, 100(1-2): 92-94.
2. Mahato SB, Sarkar SK, Poddar G: Triterpenoid saponins. Phytochemistry 1988,
27:3037-3067.
343
3. Hsu YL, Kuo PL, Lin CC: Proliferative inhibition, cell-cycle dysregulation,
344
and induction of apoptosis by ursolic acid in human non-small cell lung
345
cancer A549 cells. Life Sci 2004, 75(19): 2303-2316.
346
4. Prasad S, Yadav VR, Kannappan R, Aggarwal BB: Ursolic acid, a pentacyclin
347
triterpene, potentiates TRAIL-induced apoptosis through p53-independent
348
up-regulation of death receptors: evidence for the role of reactive oxygen
349
species and JNK. J Biol Chem 2011, 286(7): 5546-5557.
350
5. Choi YH, Baek JH, Yoo MA, Chung HY, Kim ND, Kim KW: Induction of
351
apoptosis by ursolic acid through activation of caspases and down-regulation
352
of c-IAPs in human prostate epithelial cells. Int J Oncol 2000, 17(3): 565-571.
353
6. Lee HY, Chung HY, Kim KH, Lee JJ, Kim KW: Induction of differentiation in
354
the cultured F9 teratocarcinoma stem cells by triterpene acids. J Cancer Res
355
Clin Oncol 1994, 120(9): 513-518.
356
7. Zhang T, He YM, Wang JS, Shen J, Xing YY, Xi T: Ursolic acid induces HL60
357
monocytic differentiation and upregulates C/EBPβ expression by ERK
358
pathway activation. Anticancer Drugs 2011, 22(2): 158-165.
359
8. Cha HJ, Bae SK, Lee HY, Lee OH, Sato H, Seiki M, Park BC, Kim KW:
18
360
Anti-invasive activity of ursolic acid correlates with the reduced expression of
361
matrix metalloproteinase-9 (MMP-9) in HT1080 human fibrosarcoma cells.
362
Cancer Res 1996, 56(10): 2281-2284.
363
364
9. Sohn KH, Lee HY, Chung HY, Young HS, Yi SY, Kim KW: Anti-angiogenic
activity of triterpene acids. Cancer Lett 1995, 94(2): 213-218.
365
10. Kiran MS, Viji RI, Sameer Kumar VB, Sudhakaran PR: Modulation of
366
angiogenic factors by ursolic acid. Biochem Biophys Res Commun 2008, 371(3):
367
556-560.
368
11. Cardenas C, Quesada AR, Medina MA: Effects of ursolic acid on different steps
369
of the angiogenic process. Biochem Biophys Res Commun 2004, 320(2):
370
402-408.
371
12. Ferreira Dda S, Esperandim VR, Toldo MP, Saraiva J, Cunha WR, de Albuquerque
372
S: Trypanocidal activity and acute toxicity assessment of triterpene acids.
373
Parasitol Res 2010, 106(4): 985-989.
374
13. Papahadjopoulos D, Allen TM, Gabizon A, Mayhew E, Matthay K, Huang SK,
375
Lee KD, Woodle MC, Lasic DD, Redemann C, Martin FJ: Ste rically-stabilized
376
liposomes: improve ments in pharmacokinetics and anti-tumor the rapeutic
377
efficacy. Proc Natl Acad Sci 1991, 88(24): 11460-11464.
378
14. Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D:
379
Optimizing liposomes for delivery of che motherapeutic agents to solid tumors.
380
Pharmacol Rev 1999, 51: 691-743.
381
15. Zou WW, Sun WT, Zhang N, Xu WF: Enhanced oral bioavailability and
19
382
absorption mechanism study of N3-O-Toluyl-Fluorouracil-loaded liposomes.
383
J Biomed Nanotechnol 2008, 4: 90-98.
384
16. Wang XH, Zhou SY, Qian ZZ, Zhang HL, Qiu LH, Song Z, Zhao J, Wang P, Hao
385
XS, Wang HQ: Evaluation of toxicity and single-dose pharmacokinetics of
386
intravenous ursolic acid liposomes in healthy adult volunteers and patients
387
with advanced solid tumors. Expert Opin Drug Metab Toxicol 2013, 9(2):
388
117-125.
389
17. Xia Y, Wei G, Si D, Liu C: Quantitation of ursolic acid in human plas ma by
390
ultra performance liquid chromatography ta ndem mass spectrometry and its
391
pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2011,
392
879(2): 219-224.
393
18. Pathak AK, Bhutani M, Nair AS, Ahn KS, Chakraborty A, Kadara H, Guha S,
394
Sethi G, Aggarwal BB: Ursolic acid inhibits STAT3 activation pathway leading
395
to suppression of proliferation and che mosensitization of human multiple
396
myeloma cells. Mol Cancer Res 2007, 5(9): 943-955.
397
19. Harmand PO, Duval R, Delage C, Simon A: Ursolic acid induces apoptosis
398
through mitochondrial intrinsic pathway and caspase-3 activation in M4Beu
399
melanoma cells. Int J Cancer 2005, 114(1): 1-11.
400
20. Gao N, Cheng S, Budhraja A, Gao Z, Chen J, Liu EH, Huang C, Chen D, Yang Z,
401
Liu Q, Li P, Shi X, Zhang Z: Ursolic acid induces apoptosis in human
402
leukaemia cells and exhibits anti-leukaemic activity in nude mice through the
403
PKB pathway. Br J Pharmacol 2012, 165(6): 1813-1826.
20
404
21. Li Y, Xing D, Chen Q, Chen WR: Enhance ment of chemothe rapeutic
405
agent-induced apoptosis by inhibition of NF-kappaB using ursolic acid. Int J
406
Cancer 2010, 127(2): 462-473.
407
22. Liao Q, Yang W, Jia Y, Chen X, Gao Q, Bi K: LC-MS determination and
408
pharmacokinetic studies of ursolic acid in rat plasma after administration of
409
the traditional chinese medicinal preparation Lu-Ying extract. Yakugaku
410
Zasshi 2005, 125(6): 509-515.
411
412
413
21
414
Figures
415
Figure 1. The che mical structure of ursolic acid.
416
417
Figure 2. Vital sign data for the 3 cohorts at screening and throughout the
418
infusion. (A) Body temperature, (B) respiration, (C) pulsation, (D) diastolic pressure,
419
and (E) systolic pressure at the 3 different doses: 56 mg/m2 (n = 3), 74 mg/m2 (n = 14),
420
and 98 mg/m2 (n = 4), (mean ± SD).
421
422
423
424
425
426
427
22
428
Tables
429
Table 1. Patient characteristics at baseline.
PatientsSubjects
Characteristic
56 mg/m2 (n = 3) 74 mg/m2 (n = 14) 98 mg/m2 (n = 4)
Gender, n
Male
1
4
2
Female
2
10
2
Median age (range)
57 (49–59)
40.5 (19–68)
53.5 (42–59)
ECOG PS, n
0
2
9
1
1
1
4
3
2
1
Type of tumor, n
Non-Hodgkin
lymphoma
1
3
1
Hodgkin lymphoma
5
Renal carcinoma
1
HepatomaHepatocellular
carcinoma
1
Gallbladder carcinoma
1
Breast cancer
1
1
Lung cancer
2
Other
4
Prior therapy, n
Surgery
0
7
2
Radiotherapy
3
7
1
Chemotherapy
0
2
1
Other therapy
0
11
3
ECOG: Eastern Cooperative Oncology Group; PS: performance status
430
431
432
433
434
435
23
436
437
Table 2. Incidence of treatment-related adverse events.
Nu mber of patientssubjects
AE, N
2
56 mg/ m (n = 3)
2
74 mg/ m (n = 14)
98 mg/ m2 (n = 4)
Total (n = 21)
G1
G2
≥G3
G1
G2
≥G3
G1
G2
≥ G3
G1
G2
≥ G3
AST
-
-
-
1
-
-
-
-
-
1 (5%)
-
-
ALT
-
1
-
-
-
-
-
-
-
-
1 (5%)
-
GGT
-
1
-
-
1
-
-
1
-
-
3 (14%)
-
TG
-
-
-
1
-
-
-
-
-
1 (5%)
-
-
distention
1
-
-
1
-
-
-
-
-
2 (10%)
-
-
Pruritus
-
-
-
1
-
-
-
-
-
1 (5%)
-
-
Arthralgia
-
-
-
1
-
-
-
-
-
1 (5%)
-
-
Low-grade fever
3
-
-
-
-
-
-
-
-
3 (14%)
-
-
Hypokalemia
-
-
-
1
-
-
-
-
-
1 (5%)
-
-
Hepatotoxicity
Abdominal
G1, G2, and G3 represent grade 1, grade 2, and grade 3 respectively, according to NCI-CTC grades.
AE: adverse event; -: no occurrence.
438
439
440
441
442
443
444
445
446
447
448
449
24
450
451
Table 3. Ursolic acid liposome pharmacokinetic parameters for the 1st and 14th
452
days (mean ± standard deviation, SD; n = 8).
Parameter
Day 1
Mean ± SD
4.58
±
2.04
Unit
t1/2
h
Vd
L/m2
2
Day 14
Mean ± SD
4.00
±
1.27
88.60
±
31.80
89.90
±
28.10
CL
L/(h·m )
14.40
±
3.94
15.80
±
3.05
AUC(0-t)
ng·h/mL
5172
±
1136
4705
±
873
AUC(0-∞)
ng·h/mL
5498
±
1525
4834
±
933
MRT(0-t)
h
3.34
±
0.55
3.30
±
0.31
MRT(0-∞)
h
4.31
±
1.89
3.78
±
0.70
Tmax
h
3.00
±
1.41
3.63
±
1.06
Cmax
ng/mL
1589
±
635
1211
±
204
453
25