DOTAREM

T. PEYROUX February 2005

Parameters contributing to contrast

proton density relaxation time T1 relaxation time T2

Contrast agents

proton density water, etc. (stomach. intestine) T1 and T2 interaction with electrons

Proton relaxation

years in vacuum seconds in presence of protons sec in presence of electrons

Paramagnetic ions
ELEMENT CONFIGURATION No. of SPINS

Ti 3+ Cr 2+ Mn 3+ Fe 2+ Fe 2+ Co 2+ Ni 2+ Cu 3+ Gd

2+

2/2 3/2 5/2 5/2 4/2 3/2 2/2 1/2 7/2

Among the metals possessing unpaired electrons, gadolinium, manganese and iron appear the most powerful with 7, 5 and 5 unpaired electrons, respectively

DOTAREM is a non specific agent

Injected intravenously, it is rapidly distributed throughout water and does not target any particular organ

Pharmacokinetic properties
DOTAREM is a small and hydrophilic complex so it has a pharmacokinetic behaviour quite similar to water-soluble X-ray contrast agent: bicompartmental model without metabolization and passive renal glomerular filtration.

IV injection

Interstitium

cellular compartment
BBB

VESSELS

Renal elimination (glomerular filtration)

T1 effect

Mz

Final T1 after paramagnetic complex injection

signal

Spontaneous T1 (without Gd)

Time

My

After injection, the complexes decrease the T1 time

Prolactinoma

Pre-contrast

Post-DOTAREM

68 y/o man with headache A large, meningeal-based mass is seen in the right frontal lobe that is dark on T1-weighted image. With Gadolinium, marked homogeneous enhancement is seen in the mass.

T1-weighted without contrast agent

T1-weighted with gadolinium

DOTAREM is a gadolinium complex

O N .... ..H .. .... O .Gd ...... O .. .. N N . N
3 +
_ __ ___ ______ __________ ____________ _ __ ___ ______ __________ ____________

O-

_ __ ___ ______ __________ ____________

O=C

_ __ ___ ______ __________ ____________

C=O

OC
=

with paramagnetic properties

DOTAREM is a gadolinium complex

Why a complex and not a simple gadolinium salt?

H2O Gd3+ Gd3+

- higher relaxivity - more interaction with water - highly toxic LD 50 mouse: 0.4 mmol/kg LD 50 rat: 1.6 mmol/kg i.p.

- lower relaxivity - reduced H2O binding sites - improved tolerance LD 50 mouse: 10.6 mmol/kg LD 50 rat: > 12.5 mmol/kg

Why is gadolinium toxic?

Gd3+

Ca2+

diameter of ionic sphere 1.02 A

diameter of ionic sphere 0.99 A

1. Calcium antagonistic effect: no intrinsic activity on calcium channel: myocardial contraction, ATPase, inhibition of coagulation, cellular respiratory system, reduction of calcium. 2. precipitation of Gd(HO)3 at a pH above 6.4: RES blockage

Chemical structure of the complexes

-

O OC

N N

N
3 +

COO-

O OC

OH

Gd

N N

N N

O OC

N CO O
-

Gd3+

O OC

COO-

DOTA-Gd
(DOTAREM)
-

HP-DO3A-Gd
(PROHANCE)
O H N CH3 CH3 N N COO- COO O H N CH3 COO-

OO C OOC

Gd3+

N COO-

COOCOO
-

DTPA-Gd
(MAGNEVIST)
O N COOCOON N COO
-

COOCOO2

H2N+ HO HO H O HO HO

DTPA-BMA-Gd
(OMNISCAN)

Gd3+

Gd3+

BOPTA-Gd
(MULTIHANCE)

Chemical structure of the complexes (contd)

Gadoversetamide (Optimark)

Scientific name
dimeglumine gadopentate

Two classes of Gadolinium chelates available structure areCommercial name Company

linear / ionic Gd-DTPA linear / nonionic Gd-DTPA BMA
Linear / ionic

Magnevist Omniscan Multihance DOTAREM Optimark

Schering
GE Healthcare

gadodiamide dimeglumine gadobenate

Gd-BOPTA
Macrocyclic/ionic Gd-DOTA
Linear / nonionic

Bracco

meglumine gadoterate
gadoversetamide

Guerbet
Tyco

Relaxivity
Gadolinium complexes have equivalent paramagnetic efficacy

Complexes
Gd-DOTA (DOTAREM) Gd-DTPA (Magnevist) Gd-HP DO3A (Prohance) Gd-DTPA BMA (Omniscan) Gd-BOPTA (Multihance)

Blood Variation r1 (T1) T1 (msec) (%) 3.4 3.44 3.7 3.9 4.39 24.5 20.4 18.5 18.5 10.3 97.95 98.30 98.45 98.45 99.74

Viscosity

Viscosity Viscosity 20C 37C (mPa.s) (mPa.s) Multihance Magnevist DOTAREM Omniscan Prohance 4.9 3.2 2.8 2.0 5.3 2.9 2.0 1.9 1.3

0.5 M

Is osmolality a problem in MRI?

Osmolality
The increase in plasmatic osmolality following injection of an MRI contrast agent is much lower than that induced by even a low osmolality iodinated agent. Osmolality (mOsm/kg) Gd-BOPTA Gd-DTPA Gd-DOTA Gd-DTPA BMA Gd-HP DO3A 1970 1940 1350 789 630 2160 600 Osmotic load* (mOsm) 27.4 27.0 18.9 11.0 8.8 302.4 84
Increase in plasmatic osmolality** (mOsm/kg)

0.5 M

1.5 1.5 1.1 0.6 0.5 17.28 4.8

iodinated HOCM 350 gI/L iodinated LOCM 320 gI/L

* clinical dose = 0.2 ml/kg (MRI) or 2 ml/kg (X-ray) **supposing an instantaneous distribution of the extracellular water

Complex dissociation

Gd[Ligand]

[Ligand] + Gd3+

Stability of Gd complexes
Complexes
Gd-DOTA (DOTAREM) Gadoversetamide (Optimark) Gd-BOPTA (Multihance) Gd-DTPA (Magnevist) Gd-DTPA BMA (Omniscan)

Thermodynamic stability (logK)

25.8 16.6 22.6 22.1 16.9

Apparent stability pH 7.4 (logK)

18.8 14.9 18.4 17.7 14.9

Half-life in a 0.1M HCL acid solution

up to 1 month NA NA 10 min. 30 sec

(Tweedle M.F. Invest. Radiology, 1992; vol 27 suppl 1/S2-6)

DOTAREM, macrocyclic and ionic, is the most stable, irrespective of the measurement method

Transmetallation
Complexes
Gd-DTPA (Magnevist) Gd-DTPA BMA (Omniscan) Gd-HP DO3A (Prohance) Gd-DOTA (DOTAREM)

Zn2+ Cu2+ (2mM, 15 min) (2 mM, 15 min)

21 % 25 % < 1% <1% 25 % 35 % <1% <1%

The more stable the complex, the lower the number of dissociation and exchange reactions with endogenous ions (transmetallation)

What is Transmetallation?
Gd[Ligand] + Mex+ Me[Ligand] + Gd3+

If we add electrolytes to a gadolinium complex, these metal ions interact with the ligand chelator and tend to liberate free gadolinium.
Macrocycles have a reduced transmetallation and are thus more stable

% Retention in the femur at 14 days

(Mice, 0.4 mmol/kg)

0,1 0,08 0,06 0,04 0,02 0

Tweedle 1992

< sens
DOTA

< sens
DTPA DTPA BMA

HP DO3A

Advantages of DOTAREM

Stability and transmetallation

DOTAREM, Gd-DOTA, macrocyclic and ionic is the most stable Gd3+ complex with the lowest risk of transmetallation

Interference with calcium measurement

(J. Lin et coll. 1999)
2 0

Change in UV absorbance

-2 -4 -6 -8 -10 -12 -14 -16 -18

Variation (in %) of UV absorbance of O-cresol-phtalein (commercial solution) at 572 nm over time in the presence of Gd-DOTA (2,5 mM) or Gd-DTPA-BMA (2,5 mM). OCP/Gd-DTPA-BMA OCP/Gd-DOTA OCP alone

time (sec)

OCP/Gd-DTPA-BMA OCP/Gd-DOTA OCP alone

Change in UV absorbance

Variation (in %) of UV absorbance of methylthymol blue (commercial solution) at 612 nm over time in the presence of Gd-DOTA (2,5 mM) or Gd-DTPA-BMA (2,5 mM).

49 44 39 34 29 24 19 14 9 4 -1

time (sec)

Interference with calcium measurement

(J. Lin et coll. 1999)

Change in UV absorbance

False critical Hypocalcemia following Gadodiamide Infusion

(Hale E. EREL & coll. 2002)
Retrospective study (22-month period): 1049 patients Spurious hypocalcemia in the majority of the patients Critical hypocalcemia (<6 mg/dl): 33 patients (3.1%)

18 treatments 7 (IV) 11 (oral)

Pharmaceutical formulations of the different commercial solutions

Commercial solutions Pharmaceutical formulations No Ca2+ complex added 0.1 % in moles of Ca2+ HP DO3A calcium salt 0.2 % in moles of DTPA meglumine salt 5 % in moles of Ca2+ DTPA BMA sodium salt

DOTAREM PROHANCE MAGNEVIST OMNISCAN

MACROCYCLIC / LINEAR (stability)

is a better classification than

IONIC / NON-IONIC (osmolality)

DOTAREM Tolerance

Studies Caill's paper (1991) Oudkerk's paper (1995)

Patients 4169 1038

Adverse events 0.84 % 0.97 %

Indications
(according to the countries)

Central Nervous System

Prolactinoma

Pre-contrast

Post-DOTAREM

A 56-year-old female patient with a history of myeloma. Diplopia and left exophthalmus developed in four days. Axial T1- and T2-weighted sequences showed an extra conal tumoral process in the superior lateral left orbit that lowered the globe. After injection of Dotarem, the lesion markedly enhanced whereas no intracranial involvement or meningeal uptake was visualised. Biopsy diagnosed a plasmacytoma

axial T1 w. sequence

axial T1 post DOTAREM

Leptomeningeal metastases

Post-DOTAREM

Assessment of low back pain with fever in a Pakistani male patient. T1- and T2-weighted sequences were used, and a T1-weighted sequence after injection of Dotarem. Tuberculous spondylitis with paravertebral abscesses were easily diagnosed. The epidural abscess was clearly visible after injection of Dotarem.

sagital T1w. sequence

sagital T1 post DOTAREM

Indications
(according to the countries)

Central Nervous System Whole Body (abdomen, kidneys, pelvis, heart, mammae, joint diseases)

Dynamic imaging

Dynamic MRI of left breast

Bone-joint examinations

Pre-contrast

Post-Dotarem

20-year-old man with right femoral pain with nocturnal recrudescence

Bone-joint examinations
A 47-year-old immunodepressed male patient presented with a painful swelling on the medial left knee in a context of deteriorated general health status. T2-, T1- and fat-suppressed proton-densityweighted sequences (1 to 4) showed both bone and joint involvement. The sequences after injection of Dotarem (5 and 6) showed epiphyseal and synovial contrast uptake. Biopsy resulted in a diagnosis tuberculosis osteomyelitis and arthritis.

sagital T1 w. sequence

sagital T1 post DOTAREM

Bone-joint examinations
(cont'd)

Pre-contrast

Post-Dotarem

25-year-old patient with inflammatory knee pain

Indications
(according to the countries)

Central Nervous System Whole Body (abdomen, kidneys, pelvis, heart, mammae, joint diseases) Angiography

Peripheral angiography

58-year-old patient with diabetes mellitus and peripheral arterial disease

Postoperative assessment of a femoro-femoral bypass in a 55-year-old patient.

Peripheral angiography
A 72-year-old male patient, a heavy smoker, presented with left intermittent claudication beyond a 500-metre range. The examination showed that the left femoral pulse was reduced and the systolic blood pressure of the lower limbs was four points lower on the left side. MR angiography carried out with a bolus injection of 20 cc of Dotarem shows a very short pre-occlusive stenosis at the origin of the left common iliac artery and stenoses of both internal iliac arteries. Images of the distal bed only showed moderate infiltration of the arteries without significant stenosis. Thus, the patient was scheduled for angioplasty of the left common iliac artery.

iliac MRA

thigh MRA

legs MRA

Carotid arteries imaging

TOF MR angiography fails to provide sufficient diagnostic information

Contrast enhanced MR angiography

Renal imaging

41-year-old male patient with renal insufficiency and hypertension

Renal transplantation follow-up

Patient with severe atherosclerosis, arrows indicate bilateral renal artery sclerosis

Posology and method of administration

(according to the countries)

The standard dose is 0.1 mmol/kg i.e. 0.2 ml/kg Angiography: a second injection of 0.2 ml/kg may be administered during the same session if necessary Cerebral explorations in oncology: a second injection of 0.4 ml/kg can be administered

DOTAREM is the first product to have obtained MR Angiography indication

DOTAREM A large range of packaging forms

(according to the countries)

Vials: 5 ml, 10 ml, 15 ml, 20 ml, 60 ml, 100 ml Prefilled syringes: 15 ml, 20 ml Future (to be determined) - 10 ml prefilled syringe - 40 ml vial

DOTAREM
Used in more than 5 Million examinations Extremely well tolerated For all ages, whole body and angiography (according to the countries) A large range of packaging forms Compatible with all new sequences

Comparison Dotarem / competitors (1)

Trademark Dotarem Guerbet Magnevist Schering Gd-DTPA Linear ionic 1960 2.9 22.1 Vials : 5, 10, 15, 20, 30 & 100 ml Syringes :10, 15 & 20 ml Omniscan Amersham Gd-DTPA BMP Linear non ionic 650 1.4 16.9 Multihance Bracco/Altana Gd-BOPTA Linear ionic 1970 5.4 22.6 OptiMARK Tyco Gadoversetamide Linear nonionic 1110 2 16.6 Vials: 5,10,15 & 20 ml Syringes: 10,15,20 & 30 ml

Scientific name Gd-DOTA Structure nature Macrocyclic ionic Osmolality mOsm/kg Viscosity at 37C Thermodyn. Stability Practical Packaging 1350 2.0 25.8 Vials : 5, 10, 15, 20, 60 & 100 ml Syringes : 15 & 20 ml

Vials : 5, 10, 15, Vials : 5, 10, 15 20, 50 ml & 20 ml Syringes : 10, 15 & 20 ml

Comparison Dotarem /
c me rs(2 o p tito )
Trademark Dotarem Guerbet Magnevist Schering Adults Children Infants - Neuro - Whole body Omniscan Amersham Adults Children Infants - Neuro - Whole body - Angiography - 0.1 - 0.1 + 0.2 - 0.1 + 0.1 + 0.1 Multihance Bracco/Altana OptiMARK Tyco

Authorized administration

Adults Children Infants - Neuro - Whole body - Angiography - 0.1 - 0.1 + 0.2 - 0.1 + 0.2

Adults

Adults

Indications

- Liver lesions - Neuro - Neuro - Liver

Dosage mmol/kg

- 0.1 - 0.1 + 0.1 - 0.3

- Liver: 0.05 - CNS: 0.1

- 0.1

Comparison Dotarem / competitors (3)

Trademark Dotarem Guerbet 0 Magnevist Schering Haemolitic anaemia Omniscan Amersham 0 Multihance Bracco/Altana - Severe renal failure - Pregnant women OptiMARK Tyco Allergy to Gd

Contra Indications (other than Gd, pacemarker, Vascul. Clip)

Special warnings & - Caution in special precautions patients with for use severe renal failure

- Observation of renal fc in patients with renal failure -Patients with convulsive antecedents

Caution in patients with several renal failure

- not Haemoglobinorecommended < pathies 18 years - Caution in patients with cardiovascular pathologies

Interaction

- Modif. Calcium dosage

- Modif. Calcium dosage

Comparison Dotarem / competitors (4)

Trademark Relaxivity r1 (mM -1 sec-1 ) water Relaxivity r1 (mM -1 sec-1 ) blood Dotarem Guerbet 3.4 Magnevist Schering 3.77 Omniscan Amersham 3.8 Multihance Bracco/Altana 4.39 OptiMARK Tyco

4.0

4.8

5.4

9.7

T1 blood (msec)

24.5

20.4

18.5

10.3

Variation (%)

97.95

98.30

98.45

99.14