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The Relevance of Paclitaxel Dose and Coating for Efficacy and Safety
Renu Virmani, MD
CVPath Institute, Inc.
Gaithersburg, Maryland, USA
Potential conflicts of interest
Speaker's name: Renu Virmani, MD I have the following potential conflicts of interest to report: Consultant: 480 Biomedical, Abbott Vascular, Medtronic, and W.L. Gore. Employment in industry: No Honorarium: 480 Biomedical, Abbott Vascular, Boston Scientific, Cordis J&J, Lutonix, Medtronic, Merck, Terumo Corporation, and W.L. Gore. Institutional grant/research support: 480 Biomedical, Abbott Vascular, Atrium, BioSensors International, Biotronik, Boston Scientific, Cordis J&J, GSK, Kona, Medtronic, MicroPort Medical, CeloNova, OrbusNeich Medical, ReCore, SINO Medical Technology, Terumo Corporation, and W.L. Gore. Owner of a healthcare company: No Stockholder of a healthcare company: No
Requirements For DCB
• Must deliver large quantities of the drug within seconds
• Must distribute within the media in the first few days
• Therapeutic drug levels must be maintained for at least several weeks
• Must allow rapid healing as compared to DES
• No need for long-term anticoagulation
• Light microscopy must show biologic effects at 28-days at least
Device Company Coating Drug dose (µg/mm2)
CE mark*
Advance 18 PTX™ Cook Medical, Bloomington, IN, USA Paclitaxel 3.0 Yes
Cotavance® Bayer Schering Pharma AG, Berlin, Germany Paclitaxel–iopromide 3.0 Yes
Freeway™ Eurocor, Bonn, Germany Paclitaxel–shellac 3.0 Yes
IN.PACT™ Admiral, Amphirion, Pacific
Medtronic Vascular, Santa Clara, CA, USA Paclitaxel–urea 3.0 Yes
Lutonix DCB® (Moxy) BARD, Murray Hill, NJ, USA Paclitaxel–polysorbate/sorbitol 2.0 Yes
Legflow® Cardionovum, Warsaw, Poland Paclitaxel–shellac 3.0 Yes
Passeo-18 Lux® Biotronik, Bülach, Switzerland Paclitaxel–butyryl-tri-hexyl citrate 3.0 No → Yes
Stellarex® Covidien, Mansfield, MA, USA Paclitaxel 2.0 No → Yes
* Lutonix DCB® and IN.PACT™ are currently approved by the FDA for clinical use in USA.
In.Pact
ELUTAX
Sequent Please
Pantera Lux
SurModics
Moxy
Drug coated balloon devices (Peripheral artery)
Byrne RA, Joner M. et al. Nat Rev Cardiol. 2014;11:13-23
Immunofluorescence micrographs showing the
effect of 1.0 μmol/L paclitaxel on cytoplasmic
microtubule distribution.
Immunofluorescence micrographs demonstrating the
effect of 1.0 μmol/L paclitaxel on the distribution of the
contractile filament smooth muscle α-actin and the
intermediate filament vimentin in haSMCs.
a-actin
vimentin
Anti-b-tubulin
The effect of nonstop incubation
with 1.0 μmol/L paclitaxel
on haSMC morphology.
Paclitaxel
Control
Paclitaxel-treated cultures, cell numbers are reduced.
haSMCs are smaller and discoid with a loss of tail .
Axel D I et al. Circulation 1997;96:636-645
disarrangement of α-actin bundles with
partial circumferential orientation α-actin filaments predominantly orientated
along the cell axis
changes of cell shape and size
Cells smaller, ellipsoid, and show an unorganized, decentralized
tubulin distribution
Parameters that distinguish DCB from DES
DES DCB
Drug concentration on the device
Low 5-10 μg/mm
Very High 2-3 μg/mm2 (≒20-30 μg/mm)
Drug transfer at the time of deployment
Slow Rapid, all at once
Reservoir of drug Polymer No (excipient important)
Drug retention in tissues Short term Need a drug which binds to cell membranes and is easily transferable to adjacent cells
Diffusion Good Excellent
Lipophilic yes Even better
Active ingridient Not necessary Should be active immediately
DES
DCB
Histologic Parameters for Evaluation of DCB Safety/Efficacy
• Key parameters include:
– Endothelial Loss
– Fibrin/Platelets
– Inflammation
– Injury
– Medial Smooth Muscle Cell Loss
– Matrix Replacement:
• Proteoglycan
• Collagen
– Adventitial Fibrosis
Fibrin
SMC loss
Proteoglycan
Drug deliver of DEB
Unpublished Data; Pharmakokinetic and Histologic Response to a Paclitaxel Eluting Balloon (Sponsor: Kaneka Corporation) in 2009
Histology images: Nakano M, et al. Cardiology Today's Intervention 2012;1:10-11
PTX Adherence to Balloon: iopromide versus urea coating
Kelsch et al. Invest Radiol. 2011;46:255-263
* p=0.002 ** through a blood-filled hemostatic valve and guiding catheter and 1min in stirred blood *** not released during expansion in a coronary artery
Split-off during dry inflation
Loss during
passage**
Remnant on balloon after deflation ***
Paclitaxel uptake in the Arterial Wall
600 500 400 300 200 100 0
Iopromide matrix coating
Urea matrix coating
Paclitaxel uptake in arterial wall 15-25 minutes Post stent implantation (n= 6 arteries each)
Kellsch B, et al. Investigative Radiology 2011;46(4):255-63
Yazdani SK, et al. Catheter Cardiovasc Interv. 2014;83(1):132-40
μg
58.8±54.2
60 min
Lutonix, 2mg/mm2
Polysorbate+sorbitol
Lutonix , 2 mg/mm2 deployed in Swine
Femoral Artery model at 1x
Vascular, downstream, and pharmacokinetic responses to treatment with a low dose drug‐coated balloon
in a swine femoral artery model
Yazdani SK, et al. Catheter Cardiovasc Interv. 2014;83(1):132-40
Vascular changes following Lutonix DCB treatment in Porcine Iliac arteries
28-days 90-days 180-days 1x dose
Yazdani SK, et al. Catheter Cardiovasc Interv. 2014;83(1):132-40
*Medtronic data on file
Paclitaxel concentrations post-treatment support long-term efficacy*
• Detectable levels of drug up to 180 days in both arms (therapy dose and safety margin)
• At 320 no quantifiable drug is identified in the targeted tissue area
Drug in Tissue
0 5 0 1 0 0 1 5 0 2 0 0
0
2 0
4 0
6 0
8 0
D a y s
Pa
clita
xe
l c
on
ce
ntra
tio
n (n
g/m
g)
N o m in a l D o s e
3 X S a fe ty M a rg in D o s e
Porcine IleoFemoral Artery
6 0 9 0 1 2 0 1 5 0 1 8 0
0 .0 0 1
0 .0 1
0 .1
1
1 0
D a y s
Pa
clita
xe
l c
on
ce
ntra
tio
n (n
g/m
g)
N o m in a l D o s e
S a fe ty M a rg in D o s e
N = 6 / t im e p o in t
E C 5 0 P a c lita xe l
IN.PACT Drug Eluting Balloon: Medtronic
•Very mild neointimal / medial inflammation resolved by 180 days
•SMC loss at indicating pharmacological activity of paclitaxel
Preclinical Response
Neointimal / Medial Inflammation Score
Day post-Treatment
Sco
re
28 90 180 28 90 1800
1
2
3
4
*
Control
DEB
*
Neointimal Proteoglycan / Collagen Score
Day post-Treatment
Sco
re
28 90 180 28 90 1800
1
2
3
4
5Control
DEB*
Medial SMC Loss (Depth)
Day post-Treatment
Sco
re
28 90 180 28 90 1800
1
2
3
4
5
*
*Control
DEB* *
Medial SMC Loss (Circumf)
Day post-Treatment
Sco
re
28 90 180 28 90 1800
1
2
3
4
**
Control
DEB
*
Paclitaxel action
Histomorphometry of Treated Porcine Arteries*
*Medtronic data on file
IN.PACT Drug Eluting Balloon: Medtronic
1X Inflation 4X Inflations 6X Inflations Controls
Dose-dependent Changes in Iliofemoral Arteries Following SeQuent DEB treatment at 14 days
X6 inflations
Vascular Changes in Downstream Skeletal Muscle
4x Dose
1x Dose
90 Days 180 Days 28 Days
90 Days 28 Days
(None observed for 1x dose at 180 days)
(None of physiological significance observed for Moxy DCB at any time)
Safety Profile All about Balancing Safety, Efficacy and Biologic
Response Not all balloons are created equal
Effic
acy
Safe
ty
Drug Load
Use of Carrier/Excipient
Drug Retention
Repeat Inflations
More
Less
less
more
Rapid Vascular Healing
Good Re-Endothelialization
No distal Emboli
Less neointima Absence of restenosis No, early or late thrombosis
Acknowledgments
CVPath Institute
Hiroyoshi Mori, MD Kazuyuki Yahagi, MD Oscar D. Sanchez, MD Tobias R. Koppara, MD Erica Pacheco, MS Robert Kutz, MS Russ Jones Ed Acampado, DVM Youhui Liang, MD Abebe Atiso, HT Jinky Beyer Hedwig Avallone, HT Lila Adams, HT Hengying Ouyang, MD Elena Ladich, MD Frank D Kolodgie, PhD Michael Joner, MD
Washington DC