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DC beads loaded with Irinotecan :precilinical in-vitro & in-vivo evaluation
T de Baere
- Bench top- Animal model
Colorectal cancer chemotherapy
5 FU5 FU5FU-FA5FU-FA
LV5FU2LV5FU2
20 %10 %25 %
% response rate% response rate
FOLFIRIFOLFIRI
55 % 55 %
FOLFOXFOLFOX
Sytemic therapy
• Improvement in response rate, namely due to Oxaliplatinum and Irinotecan
Colorectal cancer chemotherapy
5 FU5 FU
FUDRFUDR
5FU-FA5FU-FALV5FU2LV5FU2
20 %10 %
45 %25 %
% response rate% response rateOxal.Oxal.
FOLFIRIFOLFIRI
55 % 55 %
FOLFOXFOLFOX
64 %
Sytemic therapy Intra-arterial therapy
• Intra-arterial delivery provides higher response rates• 50% of the responder to IV oxaliplatin had failed IV oxalipaltin and irinoteacn
(Boige V, Lacombe S, de Baere T - Ann Surg Oncol 2008)(Boige V, Lacombe S, de Baere T - Ann Surg Oncol 2008)
Rationale for intra-arterial route
DrugDrug% Liver % Liver
extractionextractionClearance Clearance TB (l/min)TB (l/min)
5-FU 22-45 2-5
FUDR 69-92 5-15
IRINOTECAN 38-72 9-25
MITO-C 7-18 3-5
CDDP 8-50 0.3-0.5
DOXO 45-50 -
- Rart- Rart : advantage of IA vs IV : advantage of IA vs IV -- ErEr :extraction ratio at 1st pass :extraction ratio at 1st pass- QA- QA : arterial flow : arterial flow - CL- CL : Body clearance of the drug : Body clearance of the drug
CL
Rart = QA (1 - Er )
Rationale for intra-arterial route
• Drug eluting embols Complete embolization (QA=0, Rart≈∞)
QA (L/h)
Rar
t Er24 18 12 6
101
81
61
41
21
1 0.9
0.5
0.1
CL
Rart = QA (1 - Er )
In vitro (loading)Loading capabilities of embolics with Irinotecan
Irinotecan - 25mg/ml of beads
Comparative study of chemoembolization loadable beads.Jordan O, Denys A, de Baere T, Boulens N, Doelker E. JVIR. 2010
Hepaspheres™• 100-150 m dry• 400-600 m hydrated
DC beads™• 500-700 m hydrated
In vitro (Rigidity)Loading capabilities of embolics with Irinotecan
Irinotecan - 25mg/ml of beads
Comparative study of chemoembolization loadable beads.Jordan O, Denys A, de Baere T, Boulens N, Doelker E. JVIR. 2010
Hepaspheres™• 100-150 m dry• 400-600 m hydrated
DC beads™• 500-700 m hydrated
0
5
10
15
20
Ela
sti
c m
od
ulu
s 2
0%
co
mp
r (k
Pa
)
DC Beads Hepaspheres
0
5
10
15
20
Ela
sti
c m
od
ulu
s 2
0%
co
mp
r (k
Pa
)
DC Beads Hepaspheres
0
5
10
15
20
Ela
sti
c m
od
ulu
s 2
0%
co
mp
r (
kP
a)
DC Beads Hepaspheres
0
5
10
15
20
Ela
sti
c m
od
ulu
s 2
0%
co
mp
r (
kP
a)
DC Beads Hepaspheres
0
5
10
15
20
Ela
sti
c m
od
ulu
s 2
0%
co
mp
r (
kP
a)
DC Beads Hepaspheres
Compression of a microsphere monolayer to determine elastic modulus
In vitro (Size)Loading capabilities of embolics with Irinotecan
Irinotecan - 25mg/ml of beads
Comparative study of chemoembolization loadable beads.Jordan O, Denys A, de Baere T, Boulens N, Doelker E. JVIR. 2010
• Shrinkage under irinotecan loading with return to baseline after release
0
100
200
300
400
500
600
700
DC beads/H2O DC beads/NaCl DC beads/50%Visipaque
DC beads/af tercatheter
DC beads in vial DC beads/Irino DC beads/Irinoapr¸ s libˇ ration
DC beads/Doxo DC beads/Doxoapr¸ s libˇ
Mean
dia
mete
r (m
icro
ns)
0
100
200
300
400
500
600
700
DC beads/H2O DC beads/NaCl DC beads/50%Visipaque
DC beads/af tercatheter
DC beads in vial DC beads/Irino DC beads/Irinoapr¸ s libˇ ration
DC beads/Doxo DC beads/Doxoapr¸ s libˇ
Mean
dia
mete
r (m
icro
ns)
0
100
200
300
400
500
600
700
NaCl 0.9% NaCl:Visipaque 1:1
after cat
NaCl:Visipaque1:1 cat+ comp
NaCl after Cat Irinotecan Irinotecancoloured only
Irinotecan afterlib
Doxorubicin Doxo after lib
Me
an
dia
me
ter
(mic
ron
s)
0
100
200
300
400
500
600
700
NaCl 0.9% NaCl:Visipaque 1:1
after cat
NaCl:Visipaque1:1 cat+ comp
NaCl after Cat Irinotecan Irinotecancoloured only
Irinotecan afterlib
Doxorubicin Doxo after lib
Me
an
dia
me
ter
(mic
ron
s) Hepaspheres™
• 100-150 m dry• 400-600 m hydrated
DC beads™• 500-700 m hydrated
0
5
10
15
20
Ela
sti
c m
od
ulu
s 2
0%
co
mp
r (k
Pa
)
DC Beads Hepaspheres
0
5
10
15
20
Ela
sti
c m
od
ulu
s 2
0%
co
mp
r (k
Pa
)
DC Beads Hepaspheres
0
5
10
15
20
Ela
sti
c m
od
ulu
s 2
0%
co
mp
r (
kP
a)
DC Beads Hepaspheres
0
5
10
15
20
Ela
sti
c m
od
ulu
s 2
0%
co
mp
r (
kP
a)
DC Beads Hepaspheres
0
5
10
15
20
Ela
sti
c m
od
ulu
s 2
0%
co
mp
r (
kP
a)
DC Beads Hepaspheres
In vitro (loading homogeneity)Loading capabilities of embolics with Irinotecan
Irinotecan - 25mg/ml of beads
Comparative study of chemoembolization loadable beads.Jordan O, Denys A, de Baere T, Boulens N, Doelker E. JVIR. 2010
Hepaspheres™• 100-150 m dry• 400-600 m hydrated
DC beads™• 500-700 m hydrated
Comparative study of chemoembolization loadable beads.Jordan O, Denys A, de Baere T, Boulens N, Doelker E. JVIR. 2010
DC Beads HepasheresDrug load = 93%Drug release = 102 ±11 %T75% = 66 minutes
Drug load = 90%Drug release = 95 ± 11 %T75% = 7 minutes
DC beads
Hepaspheres
In vitro (Elution/Release)
VX2 liver tumor• IV : 12 mg• IA : 12 mg
• TACE : 6-16.5 mg (m=9.35) / 100-300 microns
– Complete stasis
PharmacoKinetic CPT11 & SN38*• Venous sampling (10min - 24H)
• Tissue sampling (1, 6, 24H)– Tumor– Liver
Quantification of tumor necrosis
* SN38 is the most active metabolite of Irinotecan
In vivo
• Reduced systemic peak levels by more than 50% Lower systemic toxicity expected for a given dose
IV
IA
DEB
In vivo : venous concentrationSerum irinotecan
• Reduced systemic peak levels by more than 50% Lower systemic toxicity expected for a given dose
Taylor RR, Eur J Pharmaco Sciences 2007
In vivo : venous concentrationSerum irinotecan
• Complex SN38 pattern, but still lower systemic level for DEB
• SN38 : active metabolite through carboxylesterase in the liver
In vivo : venous concentrationSerum irinotecan
Serum SN38
0
5
10
15
20
25
30
35
40
10 20 40 60 2H 4H 6H 12H 24H
IV
IA
TACE
In vivo : Tissue concentration
IV
IA
DEB
• Higher concentration of Irinotecan in tumor at 24 hours• DEBIRI : X 10 IA• DEBIRI : X 64 IV
In vivo : Tissue concentration
At 24 hoursMed (ng/200ml)
CPT11 tumor
IV 2.73
IA 18.29
DEBIRI 174.44
In vivo : Tissue concentration
• Higher concentration of SN38 at 24 hours
SN38 in tumor tissue
0
100
200
300
400
500
600
700
800
1H 6H 24H
IV
IA
TACE
At 24 hoursMed (ng/200ml)
CPT11 tumor
SN38 tumor
IV 2.73 2.75
IA 18.29 12.32
DEBIRI 174.44 70.23
In vivo : Tissue concentration
MTT assay (in vitro) shows 50% cell survival with 50 g at 48 h, and 25 g at 72 h in CC531-lac-Z rat CRC cells
Eyol E, Clin Exp Metastasi 2008.
CRC rat model
48h Irinotecan
72h Irinotecan
Concentration (nM)
At 24 hoursMed (ng/200ml)
CPT11 tumor
SN38 tumor
IV 2.73 2.75
IA 18.29 12.32
DEBIRI 174.44 70.23
Tumor necrosis
-10%
10%
30%
50%
70%
90%
110%
1H 6H 24H
IV IA TACE
Tumor necrosis
• Baseline necrosis of 30%, usual in VX2 tumor• Equivalent percent of necrosis for IA & TACE @ 6 h• Significantly higher necrosis for TACE @ 24 h
IV
IA
DEB
Liver toxicity
• ≈ 10 fold increase in transaminases• Start to decrease as early as 24 hours
ConclusionIn vitroDC Beads can load rapidly 96% of Irinotecan
DC Beads provide a real delivery platform for Irinotecan without burst release
In vivo DEBIRI produces lower systemic exposure to Irinotecan when compare to IV or IAH injection
DEBIRI provides higher Irinotecan and SN38 concentration in tumor than IV and IAH
DEBIRI provides higher degree of tumor necrosis than IV or IAH injection of Irinotecan
In vitro (Elution/Release)
Comparative study of chemoembolization loadable beads.Jordan O, Denys A, de Baere T, Boulens N, Doelker E. JVIR. 2010
flow-through apparatus 4 (Sotax CE6; Sotax) Six parallel implant cells. Flow at 5 mL/min
Faster release under flow than under simple shaking
0%
10%
20%
30%
40%
50%
0 2 4 6 8
Time [hrs]
% d
rug
rel
ease
d
120 rpm orbital shaking
10 ml/min
5 ml/min
t50%= 1 hr
t50%= 40 min
t50%= 4.5 hrs
Flow
Colorectal cancer
•World wide incidence: 400,000 patients
•60% patients will develop liver metastases
•Surgery is feasible in only a minority of patients and most patients are treated with systemic chemotherapy.
•Patients have a poor prognosis with reported 1- and 3-year survival rates of 31% and 2.6%, respectively .
In vivo : Tissue concentration
At 24 hoursMed (ng/200ml)
CPT11 tumor
SN38 tumor
IV 2.73 2.75
IA 18.29 12.32
DEBIRI 174.44 70.23
SN38CL Liver
22.395
10.04
14.1
Activation of carboxylesterase by embolization ?