dotarem training feb 05

DOTAREM®

T. PEYROUX – February 2005

Parameters contributingto 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

µsec in presence of electrons

Paramagnetic ions

Ti2+

Cr3+

Mn2+

Fe3+

Fe2+

Co2+

Ni2+

Cu2+

Gd3+

CONFIGURATION No. of SPINSELEMENT

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

7, 5 and 5 unpaired electrons, respectively

Injected intravenously, it is rapidly distributed throughout

water and does not target any particular organ

DOTAREM is a « non specific » agent

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 passiverenal glomerular filtration.

VESSELS

BBB

cellularcompartment

IV injection

Renal elimination (glomerular filtration)

Interstitium

T1 effect

After injection, the complexes decrease the T1 time

Time

Mz

Spontaneous T1 (without Gd)

Final T1 after paramagnetic complex injection

My

signal

Prolactinoma

Pre-contrast Post-DOTAREM

68 y/o man with headacheA 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

with paramagnetic properties

=

O

Gd3+......

............

......N

N

N

N

O-

_ __ ___ ______ ______________________

_ __ ___ ______ ______________________

_ __ ___ ______ ______________________

O-

O-

O C = OO = C

=

C

C

O

_

_

_

___

____

__ _

____

____

___

____

____

__

H

DOTAREM is a gadolinium complex

Why a complex and nota simple gadolinium salt?

Gd3+

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

Gd3+

H2O

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

Why is gadolinium toxic?

Gd3+

diameter of ionic sphere1.02 A

Ca2+

diameter of ionic sphere0.99 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

Gd3+

N N

N N

OH

COO-

- O OC

- O OC

HP-DO3A-Gd(PROHANCE®)

DOTA-Gd

(DOTAREM®)

Gd3+

N N

N NCOO-- O OC

- O OC CO O -

DTPA-Gd(MAGNEVIST®)

COO-

N N NCOO--OO C

COO--OOC

Gd3+

DTPA-BMA-Gd(OMNISCAN®)

Gd3+

COO-

N N

COO-CH3

N

O

CH3N

HO

COO-

H

2HO

Gd3+

N N

COO-

OCOO-

N

COO-

COO-

COO-

CH3

H2N+

HOHO

HO

HO

BOPTA-Gd(MULTIHANCE®)

Gadoversetamide (Optimark®)

Chemical structure of the complexes (cont’d)

Two classes of Gadolinium chelates are availableScientific name structure Commercial name Company

dimegluminegadopentate

gadodiamide

gadoversetamide

linear / ionicGd-DTPA

linear / nonionicGd-DTPA BMA

Linear / nonionic

Magnevist®

Omniscan®

Optimark®

Schering

GE Healthcare

megluminegadoterate

Macrocyclic/ionicGd-DOTA

DOTAREM® Guerbet

Tyco

Multihance® BraccoLinear / ionicGd-BOPTA

dimegluminegadobenate

Relaxivity

Gadolinium complexes have equivalent paramagnetic efficacy

Complexes r1 (T1) BloodT1 (msec)

Gd-DOTA (DOTAREM®)

Gd-DTPA (Magnevist®)

Gd-HP DO3A (Prohance®)

Gd-DTPA BMA (Omniscan®)

Gd-BOPTA (Multihance®)

3.4

3.44

3.7

3.9

4.39

24.5

20.4

18.5

18.5

10.3

Variation(%)

97.95

98.30

98.45

98.45

99.74

Viscosity

-4.93.22.82.0

Viscosity20°C

(mPa.s)

Multihance®

Magnevist®

DOTAREM®

Omniscan®

Prohance®

0.5 M

5.32.92.01.91.3

Viscosity37°C

(mPa.s)

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)

Osmoticload*

(mOsm)

Increase in plasmaticosmolality**(mOsm/kg)

Gd-BOPTAGd-DTPAGd-DOTAGd-DTPA BMAGd-HP DO3A

iodinated HOCM

iodinated LOCM

0.5 M

350 gI/L

320 gI/L

197019401350 789 630

2160

600

27.427.018.911.0 8.8

302.4

84

1.51.51.10.60.5

17.28

4.8

* 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

ComplexesThermodynamic

stability(logK)

Half-lifein a 0.1M HCLacid solution

Gd-DOTA(DOTAREM®)

Gadoversetamide(Optimark)

Gd-BOPTA(Multihance)

Gd-DTPA(Magnevist)

Gd-DTPA BMA(Omniscan)

25.8

16.6

22.6

22.1

16.9

up to 1 month

NA

NA

10 min.

30 sec

Apparent stabilitypH 7.4(logK)

18.8

14.9

18.4

17.7

14.9

(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

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

ComplexesZn2+

(2mM, 15 min)Cu2+

(2 mM, 15 min)

Gd-DTPA (Magnevist®)

Gd-DTPA BMA (Omniscan®)

Gd-HP DO3A (Prohance®)

Gd-DOTA (DOTAREM®)

21 %

25 %

< 1%

< 1 %

25 %

35 %

< 1 %

< 1 %

Macrocycles have a reduced transmetallation andare thus more stable

What is Transmetallation?

Gd[Ligand] + Mex+ Me[Ligand] + Gd3+

If we add electrolytes to a gadolinium complex, thesemetal ions interact with the ligand chelator and tend toliberate free gadolinium.

% Retention in the femur at 14 days(Mice, 0.4 mmol/kg)

0

0,02

0,04

0,06

0,08

0,1

DOTA HP DO3A DTPA DTPABMA

< sens < sens

Tweedle 1992

Advantages of DOTAREM

Stability and transmetallation

DOTAREM, Gd-DOTA, macrocyclic and ionicis the most stable Gd3+ complex with the lowest

risk of transmetallation

Interference with calcium measurement(J. Lin et coll. 1999)

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

2

time (sec)

-1

4

9

14

19

24

29

34

39

44

49

time (sec)

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

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

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

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

Cha

nge

in U

V a

bsor

banc

e

Cha

nge

in U

V a

bsor

banc

e

Interference with calcium measurement(J. Lin et coll. 1999)

Ch

an

ge

in U

V a

bso

rba

nce

Retrospective study (22-month period): 1049 patients

«Spurious» hypocalcemia in the majority of the patients

«Critical» hypocalcemia (<6 mg/dl): 33 patients (3.1%)

False “critical” Hypocalcemia following Gadodiamide Infusion

(Hale E. EREL & coll. 2002)

18 treatments

7 (IV) 11 (oral)

Pharmaceutical formulations of thedifferent commercial solutions

Commercial solutions Pharmaceutical formulations

DOTAREM®

PROHANCE®

MAGNEVIST®

OMNISCAN®

No Ca2+ complex added

0.1 % in moles of Ca2+ HP DO3Acalcium salt

0.2 % in moles of DTPAmeglumine salt

5 % in moles of Ca2+ DTPA BMAsodium salt

MACROCYCLIC / LINEAR (stability)

is a better classification than

IONIC / NON-IONIC (osmolality)

Studies Patients Adverse events

Caillé's paper (1991) 4169 0.84 %

Oudkerk's paper (1995) 1038 0.97 %

DOTAREM Tolerance

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 ®



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

Dynamic imaging

Dynamic MRI of left breast

Bone-joint examinations

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

Pre-contrast Post-Dotarem

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-density-weighted 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)

25-year-old patient with inflammatory knee pain

Pre-contrast Post-Dotarem


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

Angiography


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

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

Peripheral angiography

Peripheral angiographyA 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 transplantation follow-up41-year-old male patient with renal insufficiency and hypertension

Renal imaging

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 beadministered during the same session if necessary

Cerebral explorations in oncology: a second injectionof 0.4 ml/kg can be administered

DOTAREM is the first product to have obtained

MR Angiography indication

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®

A large range of packaging forms(according to the countries)

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

DOTAREM®

Comparison Dotarem® / competitors (1)

Trademark Dotarem® Guerbet Magnevist® Schering

Omniscan® Amersham

Multihance® Bracco/Altana

OptiMARK®

Tyco

Scientific name

Gd-DOTA Gd-DTPA Gd-DTPA BMP Gd-BOPTA Gadoversetamide

Structure nature

Macrocyclic ionic Linear ionic Linear non ionic Linear ionic Linear nonionic

Osmolality mOsm/kg

1350 1960 650 1970 1110

Viscosity at 37°C

2.0 2.9 1.4 5.4 2

Thermodyn. Stability

25.8 22.1 16.9 22.6 16.6

Practical Packaging

Vials : 5, 10, 15, 20, 60 & 100 ml

Syringes :

15 & 20 ml

Vials : 5, 10, 15, 20, 30 & 100 ml

Syringes :10, 15 & 20 ml

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

Syringes : 10, 15 & 20 ml

Vials : 5, 10, 15 & 20 ml

Vials: 5,10,15 & 20 ml

Syringes: 10,15,20 & 30 ml


Trademark Dotarem®

GuerbetMagnevist® Schering

Omniscan® Amersham

Multihance ® Bracco/Altana

OptiMARK®

Tyco

Authorized administration

Adults

Children

Infants

Adults

Children

Infants

Adults

Children

Infants

Adults Adults

Indications - Neuro- Whole body- Angiography

- Neuro- Whole body

- Neuro- Whole body- Angiography

- Liver lesions- Neuro

- Neuro - Liver

Dosage mmol/kg

- 0.1- 0.1 + 0.2- 0.1 + 0.2

- 0.1- 0.1 + 0.1- 0.3

- 0.1- 0.1 + 0.2- 0.1 + 0.1 + 0.1

- Liver: 0.05

- CNS: 0.1

- 0.1


Trademark Dotarem®


Omniscan® Amersham

Multihance ® Bracco/Altana

OptiMARK®

Tyco

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

0 Haemolitic anaemia

0 - Severe renal failure- Pregnant women

Allergy to Gd

Special warnings & special precautions for use

- Caution in patients with severe renal failure

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

Caution in patients with several renal failure

- not recommended < 18 years- Caution in patients with cardiovascular pathologies

Haemoglobino-pathies

Interaction - Modif. Calcium dosage

- Modif. Calcium dosage


Trademark Dotarem®


Omniscan® Amersham

Multihance® Bracco/Altana

OptiMARK®

Tyco

Relaxivity r1 (mM -1 sec-1) water

3.4 3.77 3.8 4.39

Relaxivity r1 (mM -1 sec-1) blood

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

dotarem training feb 05

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