1. DC beads loaded with Irinotecan : precilinical in-vitro & in-vivo evaluation
T de Baere
Bench top
Animal model

2. Colorectal cancer chemotherapy
% response rate
FOLFIRI
FOLFOX
LV5FU2
5FU-FA
55 %
55 %
5 FU
25 %
20 %
10 %
Sytemic therapy
Improvement in response rate, namely due to Oxaliplatinum and Irinotecan

3. Colorectal cancer chemotherapy
% response rate
Oxal.
FOLFIRI
FOLFOX
FUDR
LV5FU2
64 %
5FU-FA
55 %
55 %
5 FU
45 %
25 %
20 %
10 %
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)

4. Rationale for intra-arterial route
Drug
% Liver extraction
Clearance 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
DOXO
45-50 - CL
Rart =
QA (1 - Er )
- Rart : advantage of IA vs IV - Er :extraction ratio at 1st pass
- QA : arterial flow CL : Body clearance of the drug

5. Rationale for intra-arterial route
QA (L/h)
Rart Er 24 18 12 6
101 81 61 41 21 1
0.9
0.5
0.1 CL
Rart =
QA (1 - Er )
Drug eluting embols
Complete embolization (QA=0, Rart≈∞)

6. In vitro (loading) Loading capabilities of embolics with Irinotecan
Irinotecan - 25mg/ml of beads
 DC beads™
mm hydrated
 Hepaspheres™
mm dry
mm hydrated
Comparative study of chemoembolization loadable beads.
Jordan O, Denys A, de Baere T, Boulens N, Doelker E. JVIR. 2010

7. In vitro (Rigidity) Loading capabilities of embolics with Irinotecan
Irinotecan - 25mg/ml of beads
 DC beads™
mm hydrated
 Hepaspheres™
mm dry
mm hydrated
Compression of a microsphere monolayer to determine elastic modulus
Comparative study of chemoembolization loadable beads.
Jordan O, Denys A, de Baere T, Boulens N, Doelker E. JVIR. 2010

8. In vitro (Size) Loading capabilities of embolics with Irinotecan
Irinotecan - 25mg/ml of beads
 DC beads™
mm hydrated
 Hepaspheres™
mm dry
mm hydrated
Shrinkage under irinotecan loading with return to baseline after release
Comparative study of chemoembolization loadable beads.
Jordan O, Denys A, de Baere T, Boulens N, Doelker E. JVIR. 2010

9. In vitro (loading homogeneity)
Loading capabilities of embolics with Irinotecan
Irinotecan - 25mg/ml of beads
 DC beads™
mm hydrated
 Hepaspheres™
mm dry
mm hydrated
Comparative study of chemoembolization loadable beads.
Jordan O, Denys A, de Baere T, Boulens N, Doelker E. JVIR. 2010

10. In vitro (Elution/Release)
 Hepaspheres
 DC beads
DC Beads
Hepasheres
Drug load = 93%
Drug release = 102 ±11 %
T75% = 66 minutes
Drug load = 90%
Drug release = 95 ± 11 %
T75% = 7 minutes
Comparative study of chemoembolization loadable beads.
Jordan O, Denys A, de Baere T, Boulens N, Doelker E. JVIR. 2010

11. In vivo VX2 liver tumor PharmacoKinetic CPT11 & SN38*
IV : 12 mg
IA : 12 mg
TACE : mg (m=9.35) / 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

12. In vivo : venous concentration
Serum irinotecan IV IA
DEB
Reduced systemic peak levels by more than 50%
Lower systemic toxicity expected for a given dose

13. In vivo : venous concentration
Serum irinotecan
Taylor RR, Eur J Pharmaco Sciences 2007
Reduced systemic peak levels by more than 50%
Lower systemic toxicity expected for a given dose

14. In vivo : venous concentration
Serum irinotecan
Complex SN38 pattern, but still lower systemic level for DEB
SN38 : active metabolite through carboxylesterase in the liver

15. In vivo : Tissue concentrationIA
DEB

16. In vivo : Tissue concentration
At 24 hours
Med (ng/200ml)
CPT11 tumor IV
2.73 IA
18.29
DEBIRI
174.44
Higher concentration of Irinotecan in tumor at 24 hours
DEBIRI : X 10 IA
DEBIRI : X 64 IV

17. In vivo : Tissue concentration
At 24 hours
Med (ng/200ml)
CPT11 tumor
SN38
tumor IV
2.73
2.75 IA
18.29
12.32
DEBIRI
174.44
70.23
Higher concentration of SN38 at 24 hours

18. In vivo : Tissue concentration
CRC rat model
 48h Irinotecan
 72h Irinotecan
Concentration (nM)
At 24 hours
Med (ng/200ml)
CPT11 tumor
SN38
tumor IV
2.73
2.75 IA
18.29
12.32
DEBIRI
174.44
70.23
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.

19. Tumor necrosis IV IA DEB Baseline necrosis of 30%, usual in VX2 tumor
Equivalent percent of necrosis for IA & 6 h
Significantly higher necrosis for 24 h

20. Liver toxicity ≈ 10 fold increase in transaminases
Start to decrease as early as 24 hours 20

21. Conclusion In vitro DC 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 21

23. In vitro (Elution/Release)
Flow
In vitro (Elution/Release)
flow-through apparatus 4 (Sotax CE6; Sotax)
Six parallel implant cells. Flow at 5 mL/min
Faster release under flow than under simple shaking
Comparative study of chemoembolization loadable beads.
Jordan O, Denys A, de Baere T, Boulens N, Doelker E. JVIR. 2010

24. 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 .

25. In vivo : Tissue concentration
At 24 hours
Med (ng/200ml)
CPT11 tumor
SN38 tumor IV
2.73
2.75 IA
18.29
12.32
DEBIRI
174.44
70.23
SN38
CL Liver
22.395
10.04
14.1
Activation of carboxylesterase by embolization ?