Date post: | 27-Mar-2015 |
Category: |
Documents |
Upload: | dominic-alexander |
View: | 214 times |
Download: | 1 times |
Overview of Current and future Contrast Agent
andStatistical and design issues in clinical
development of contrast agents
Kohkan Shamsi, MD, PhDPresident,
Symbiotic Pharma ResearchPine Brook, NJ, USA
Former affiliation: Berlex Inc, Montville, NJ
Current Imaging Techniques• X-rays
• Ultrasonography
• Computed Tomography (CT)
• Magnetic Resonance Imaging (MRI)
• Nuclear Medicine (SPECT/PET)
• combination e.g. PET-CT
Iodinated contrast agents
• Agents come in different concentrations:• Denoted by number after name (e.g. Ultravist
300)• Number indicates mg iodine / mL of solution
• Different brands have different concentrations most common used conc. is 300mg/mL• extensively used in Computer tomography• Computer tomography is very widely used technique
The MRI-Contrast Agents
Extracellular CM Blood-Pool CMTargeted/
Intracellular CM Targeted CM
* MagnevistOMNISCAN
Optimark
+ Gadovist 1.0
Protein-bindingMS 325BR 22
MacromolecularGadomer
P792
High-Reflexivity CMUSPIO
SupravistCombidex
Hepatocyte-specific+ PrimovistMultihance
Fibrin-targetedEP-2104
RES-specific+ Resovist
Plaque-imagingGadofluorin
+ RES-specific* Feridex
MRI CM
* Approved in the USA
+ Approved in Europe
Early Stage
Gadolinium: first MR contrast agent
Magnevist was first MR contrast agent>60 million injection experience gadolinium compounds are very safe
MR Blood-Pool Agents
Extracellular Contrast Agentse.g. Magnevist
Intravascular Contrast Agents
Ec
Ec
Ec
Ec
Ec
Ec
Ec
Ec
Ec
Ec
Ec
Ec
Ec
IvIv
IvIv
Iv
Iv
USPIO
ltrasmall uper-aramagnetic ron xide particles,coated withcarboxydextran
Optimized formulation for T1 w-imaging (MRA)
USPIO
60 nm
20 nm
SPIO
7 000 nmErythrocyte
USPIO
Blood-Pool Agents Gd-Based
GadoliniumChelates
(Paramagnetic)
Strong Protein Binding Macro-Molecules (no PB)
MS-325SAG/Epix
B-22956/1Bracco
Gadomer 17Schering
P-792Guerbet
No contrast agent has been approved by FDA for MRA
Potential indications for blood pool agents
Potential indications•MRA•Cardiac•Tumor angiogenesis•Venography•Open magnets (interventions)•GI bleeding•Neurological applications•Whole body imaging•Other?
MS-325 enhanced MRI
High resolution MRA: imaging of vessel wall
Targeted agents
for cells and for structures
Liver-specific MRI-CM
“Whiteners“Whiteners“ Imaging with T1-Effect
Multihance® (Gd-BOPTA) Teslascan® (Mn-DPDP) Primovist ® (Gd-EOB-DTPA)
Specific CM for Hepatocytes
Specific CM for RES
“Blackeners“ Imaging with T2-Effect
Feridex® (SPIO) Resovist® (SHU 555 A)
Metastases
Pre T1-GRE
Post Mn-DP T1-GRE
Pre FSE T2
Mangofodipir trisodium (Mn-DpDp):
Gd-BOPTA enhanced MRI and liver metastases
PRE-DOSEPRE-DOSE
POST-DOSEPOST-DOSE
40 min40 min 120 min120 min
Courtesy of: R. Caudana,Verona, Italy
Metastases: Gd-EOB-DTPA enhanced MRI
T1 w precontrast Flash 3 D postinjection (10min)additional metastasis (blue arrow)
Courtesy of Prof. Hosten, Greifswald, Germany
Hemangioma with hepatocyte specific contrast agent (Gd-EOB-DTPA)
T1w VIBE art
T2w VIBE pv
VIBE 20 min
T1w 20 min
precontrast dynamic hepatocyte phase
Courtesy of C. Czech, Munich, Germany
page 17
Pre T1Pre T2
Post T2
Metastases
Resovist® Lesion Detection
Robinson, MD, Leeds, UK
Thrombus enhancing agent P-2104R Indications
Pulmonary Embolism (PE)
Deep venous thrombosis (DVT)
Thrombus in left atrial appendage
Venous coronary bypass grafts (CABG)
Sinus vein thrombosis
Mesenteric and portal thrombosis or emboli
aortaaorta
1h1h
thrombusthrombusPlaque in Balloon-injured rabbits after high-cholesterol(Mcdonanld) dietCourtesy :Johnstone et al, Beth Israel/Deaconess Medical Center
Plaque imaging: Gadofluorine M
New water soluble, macrocyclic gadolinium chelates Micelle formation and longer half life, high relaxivity
Plaque Imaging Gadofluorine M WHHL Rabbit
IR turbo FLASH (300/4/120/20°)
24 h post injection
Immune-Mediated Nerve Injury (EAN)6d after EAN, 24h after Gadofluorine,thigh
Peripheral Nerve Imaging
Potential applications: Structural nerve damage in Polyneuropathies Nerve trauma, Visualization of the progress of Nerve regeneration
Clinical trial design issues• Dose finding in dynamic changing technology environment
▪ minimal effective dose identification that is based on development of machines
• Efficacy criteria: sensitivity, specificity and accuracy vs. ROC
▪ interpretation of the data▪ inter reader variability (kappa statistics)▪ clinical practice vs. blinded read. FDA looks only at the BR
data▪ standard of reference (is usually old and is not really gold)▪ lesion tracking across test modalities and SOR
3-4 efficacy evaluations for each patient (site evaluation + 2-3 blinded reader evaluation) leads to multiple primary endpoints (e.g. 3 sensitivities, 3 specificities and 3 accuracies lead to multiple permutation and combinations