mri cm

Overview of Current and future Contrast Agent and Statistical and design issues in clinical development of contrast agents Kohkan Shamsi, MD, PhD President, Symbiotic Pharma Research Pine 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 MRI CM Extracellular CM Blood-Pool CM Targeted/Intracell ular CM Targeted CM * Magnevist OMNISCAN Optimark Protein-binding MS 325 BR 22 Hepatocyte-specific + Primovist Multihance Fibrin-targeted EP-2104 + Gadovist 1.0 Macromolecular Gadomer P792 RES-specific + Resovist Plaque-imaging Gadofluorin High-Reflexivity CM USPIO Supravist Combidex + RES-specific * Feridex * 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 Iv Iv Ec Iv Ec Iv Extracellular Contrast Agents e.g Magnevist Iv Ec Iv Ec Ec Ec Ec Ec Ec Ec Ec Ec Ec MR Blood-Pool Agents Intravascular Contrast Agents USPIO SPIO Erythrocyte USPIO 20 nm 60 nm 000 nm Ultrasmall S uperP aramagnetic I ron Oxide particles, coated with carboxydextran Optimized formulation for T1 w-imaging (MRA) Blood-Pool Agents Gd-Based Gadolinium Chelates (Paramagnetic) Strong Protein Binding Macro-Molecules (no PB) MS-325 SAG/Epix Gadomer 17 Schering B-22956/1 Bracco P-792 Guerbet 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 “Blackeners“ Imaging with T2-Effect “Whiteners“ Imaging with T1-Effect Feridex® (SPIO) Resovist® (SHU 555 A) Multihance® (Gd-BOPTA) Teslascan® (Mn-DPDP) Primovist ® (Gd-EOB-DTPA) Specific CM for RES Specific CM for Hepatocytes Mangofodipir trisodium  (Mn­DpDp): Pre T1-GRE Pre FSE T2 Metastases Post Mn-DP T1-GRE Gd-BOPTA enhanced MRI and liver metastases Courtesy of: R Caudana,Verona, Italy PRE-DOSE POST-DOSE 40 120 Metastases: Gd-EOB-DTPA enhanced MRI T1 w precontrast Flash D postinjection (10min) additional metastasis (blue arrow) Courtesy of Prof Hosten, Greifswald, Germany Hemangioma with hepatocyte specific contrast agent (Gd-EOBDTPA) T1w T2w precontrast VIBE art VIBE 20 VIBE pv T1w 20 dynamic hepatocyte phase page 17 Courtesy of C Czech, Munich, Germany Resovist® Pre T1 Post T2 Lesion Detection Pre T2 Metastases 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 aorta thrombus 1h Plaque in Balloon-injured rabbits after high-cholesterol(Mcdonanld) diet Courtesy : 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 24 h post injection IR turbo FLASH (300/4/120/20°) Peripheral Nerve Imaging Immune-Mediated Nerve Injury (EAN) 6d after EAN, 24h after Gadofluorine, thigh  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 sensitivities, specificities and accuracies lead to multiple permutation and combinations ... Computer tomography is very widely used technique The MRI- Contrast Agents MRI CM Extracellular CM Blood-Pool CM Targeted/Intracell ular CM Targeted CM * Magnevist OMNISCAN Optimark Protein-binding... •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 “Blackeners“ Imaging with T2-Effect “Whiteners“... ® (Gd-EOB-DTPA) Specific CM for RES Specific CM for Hepatocytes Mangofodipir trisodium  (Mn­DpDp): Pre T1-GRE Pre FSE T2 Metastases Post Mn-DP T1-GRE Gd-BOPTA enhanced MRI and liver metastases