DC beads loaded with Irinotecan : precilinical in-vitro & in-vivo evaluation

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





0

5

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20

Ela

sti

c m

od

ulu

s 2

0%

co

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r (k

Pa

)

DC Beads Hepaspheres

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)


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Compression of a microsphere monolayer to determine elastic modulus

In vitro (Size)Loading capabilities of embolics with Irinotecan



• 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


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0

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Ela

sti

c m

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r (

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0

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0%

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In vitro (loading homogeneity)Loading capabilities of embolics with Irinotecan






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


• Complex SN38 pattern, but still lower systemic level for DEB

• SN38 : active metabolite through carboxylesterase in the liver


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


At 24 hoursMed (ng/200ml)

CPT11 tumor

IV 2.73

IA 18.29

DEBIRI 174.44


• 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


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.

CRC rat model

48h Irinotecan

72h Irinotecan

Concentration (nM)


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)


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 .



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 ?

DC beads loaded with Irinotecan : precilinical in-vitro & in-vivo evaluation

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Transcript of DC beads loaded with Irinotecan : precilinical in-vitro & in-vivo evaluation