TELEBRIX

TRAINING SESSION

TELEBRIX RANGE Tx 35, Tx 30M, Tx 12Na

CHEMICAL STRUCTURE
R3 I I

Chemical structure Atomic number of iodine: 53

R1 I

R2

Chemical structure of ioxitalamic acid common to all contrast media: benzene ring 3 iodine atoms

Main chemical feature : - (OH) radical in position (3) Salified in sodium or meglumine salt form

CHEMICAL STRUCTURE
Advantages of -(OH) radical : Physicochemical

high solubility lower global toxicity respect of the BBB and vascular endothelium ppplower protein binding: risk of allergic-like adverse events

Related to the compounds the ioxitalamic acid is combined to :

Sodium Methylglucamine both

PHYSICO-CHEMICAL PROPERTIES
Osmolality
Proportional to the number of particles (molecules, ions) Depending on:
iodine concentration molecular weight hydrophilicity

PHYSICO-CHEMICAL PROPERTIES
Osmolality
COOM I I I COOI

M+

Na+ Meglumine+

R1 I

R2

R1 I

R2

Organic iodine salt

3 particles 3 iodine atoms

Example of a high osmolality contrast medium (HOCM)

PHYSICO-CHEMICAL PROPERTIES
Osmolality
osmolality (mOsm/kg H2 O) Telebrix 35 Telebrix 30M Telebrix 12Na Diatrizoate Plasma 2160 1500 610 1650 300

PHYSICO-CHEMICAL PROPERTIES
Osmolality
Osmotic effects of iodinated contrast agents: transfer of water Effects on blood volume

PHYSICO-CHEMICAL PROPERTIES
Diffusion and osmotic equilibrium

H2O

H2O

PHYSICO-CHEMICAL PROPERTIES
Immediate osmotic effect of iodinated contrast agents: risk of hypervolemia
Transfer of water H2O Interstitial diffusion

Tissues
H2O blood vessel INCREASED BLOOD VOLUME STATE OF EQUILIBRIUM

PHYSICO-CHEMICAL PROPERTIES
Vascular effect of osmolality
BEFORE INJECTION AFTER INJECTION

Vein

Artery

PHYSICO-CHEMICAL PROPERTIES
Contrast agent osmolality and effects on blood volume

27.6%

26.6% 19.1% 17.6% 14% 12.9%

increase in blood volume (%)

23.5%

21.9%

iopamidol

10 mn Fukao, 1990

PHYSICO-CHEMICAL PROPERTIES

Viscosity

Viscosity is measured in Cp Depends on several parameters : iodine concentration the base used to salify the acid function the proportion of salt the temperature

PHYSICO-CHEMICAL PROPERTIES
Viscosity according to temperature
Viscosity in mPa.s
50 40

Viscosity at 37C according to iodine content

30 10 20

10

15

25

35

10

20

30

40

Temperature (C)

% iodine content

IOXITALAMATE

PHYSICO-CHEMICAL PROPERTIES
Viscosity of the different ioxitalamic acid salts

PHYSICO-CHEMICAL PROPERTIES
Viscosity according to basic composition
iodine content g/100ml Telebrix 35 Telebrix 30M Telebrix 12Na Contrix 28 Radioselectan 76% Radioselectan 60% Blood
R adio-

sodium % 13 0 100 0 13 13 -

meglumine % 87 100 0 100 87 87 -

viscosity Cp at 37C 7.5 5.2 1.1 4.3 8.5

35 30 12 28 37 29 -

3.8

PHYSICO-CHEMICAL PROPERTIES
Viscosity

The image is related to the viscosity of the contrast agent the higher the viscosity the lower the dilution drawback: imaging of small vessels the low viscosity allows the imaging of these small vessels

PHYSICO-CHEMICAL PROPERTIES
Consequences

The choice of the composition of a contrast agent is a compromise between iodine content salt viscosity

According to the type of examination one of these parameters is dominating

PHYSICO-CHEMICAL PROPERTIES
Hydrophilicity

x Chemotoxicity of a contrast agent is related to the concept of hydrophilicity / lipophilicity x Measured by the octanol / water partition coefficient

PHYSICO-CHEMICAL PROPERTIES
Comparative hydrophilicity (octanol / water partition coefficient)
HYDROPHILICITY
TELEBRIX Iothalamate 2 Diatrizoate 2.5 1.3

pH = 7.4 0 = 20C

LIPOPHILICITY

PHYSICO-CHEMICAL PROPERTIES

Hydrophilicity

x Telebrix is the most hydrophilic of its class x Telebrix is the most up-to-date and sophisticated HOCM

PHYSICO-CHEMICAL PROPERTIES
Telebrix, the first hydrophilic iodinated contrast agent How ?
COOH I I I COOH I

CH3-CO-NH I

NH-CO-CH3 COOH I I

CH3-CO-NH I

CO- NH -CH3

DIATRIZOATE

IOTHALAMATE
CO-NHCH2-CH2-OH I

CH3-CO-NH

IOXITALAMATE (TELEBRIX)

PHYSICO-CHEMICAL PROPERTIES

Hydrophilicity
x Low protein binding rate: 4,8 % close to non ionic contrast agents x On a clinical point of view improved safety (local, general) increase of interstitial diffusion x Consequences on distribution volume

PHARMACOKINETIC PROFILE
A two compartment model
blood cells cells

plasma

interstitial tissue

urine

Distribution phase: pC >> iC at equilibrium: pC = iC

PHARMACOKINETIC PROFILE
Pharmacokinetic profile of Telebrix
in comparison with competitors Product Ioxitalamate (Na + Mg) Parameter V (liters/kg) (min-1) V1 (liters/kg) (min-1) 0.13 0.19 0.51 0.014 Metrizamide (nonionic) 0.10 0.22 0.29 0.015 Diatrizoate (Na + Mg) 0.11 0.13 0.27 0.014

PHARMACOKINETIC PROFILE

Distribution volume: ioxitalamate > metrizamide > diatrizoate Rapidity of diffusion: HOCM > LOCM At same osmolality, ioxitalamate diffuses better than diatrizoate hydrophilicity

SAFETY PROFILE
During pre-clinical studies
LD50 measurements
Animal Rate of injection ml/mn 0.5 Telebrix 35 g iodine/kg 8.1 Telebrix 30M g iodine/kg 6.9 Diatrizoate Telebrix 12Na

mice

5.7

NA

A lower global toxicity compared to diatrizoate A higher margin of safety

SAFETY PROFILE
During pre-clinical studies
LD 50 (intra cisternal) measurements
g of meglumine salt/kg

Telebrix

diatrizoate

Telebrix displays a better neurological safety when BBB is disrupted

SAFETY PROFILE
During clinical studies
HOCM (Telebrix excluded)
12.7 %

TELEBRIX
4.1 % 2.8 % H. Katayama (1990) H. Witt (1984) JM. Caill (1993)

NONIONIC LOCM

3,1 % 1,1 % H. Katayama U.Fink (1990) (1992)

The safety profile of Telebrix is close to nonionic's

TELEBRIX

PRODUCTS FILE

TELEBRIX 35

Osmolality Viscosity Salt

: 2160 mOsm/kg H2O : 7,5 mPa.s at 37C : Meglumine (87 %) / Na+ (13 %)

Iodine content : 35 g of iodine / 100 ml

TELEBRIX 35
CT

High osmolality and strong hydrophilicity lead to an increase of the interstitial diffusion Very good tissue opacification

TELEBRIX 35
CT
Efficacy/Safety of Telebrix 35 in CT - Dr H. Muntlak & coll.

Objective: efficacy and safety evaluation of Telebrix 35 in CT examination Material and methods: - 50 patients included for head or pelvis CT. - average dose of Telebrix 35: 100 ml Evaluation criteria: - diagnostic quality (AVS) - safety (adverse events)

TELEBRIX 35
CT

Results global diagnostic quality : 9.55 + 1.1 (out of 10) safety

* 1 nausea, 1 headache, 1 urticaria, 1 vomiting, 1 dizziness

TELEBRIX 35
CT Conclusions
With Telebrix 35

Diagnostic established in 100 % of cases Excellent patient safety (90 % with no AE or heat) Minor AE in only 10 % of cases

TELEBRIX 35
Angiography

Low viscosity of Telebrix 35

easy injection in arteries

Physiological level of Na+ concentration (148 mEg/l) Presence of edetate calcium disodium reduction of the risk of impaired myocardiac contraction

TELEBRIX 35
IVU
Efficacy/Safety of Telebrix 35 in IVU-Pr J. Drouillard & coll.

Objective: efficacy and safety evaluation of Tel. 35 in IVU Material and methods: 50 patients (8 with prior allergic like reactions) received an i.v. dose of 2 ml/kg Tel. 35 according to a 2 bolus injection (132 ml) Evaluation criteria: - diagnostic efficacy - safety (adverse events)

TELEBRIX 35
IVU

Results diagnostic efficacy : 7.98 + 1 (out of 10) safety

* 1 nausea, 1 headache, 1 urticaria, 1 vomiting, 1 dizziness

TELEBRIX 35
IVU
CONCLUSIONS

Very good quality of the images Image quality due to the high osmolality of Telebrix 35 with an efficient Na+ level (low effects on diuretic osmosis) Very good safety profile due to the hydrophilicity of the agent

TELEBRIX 30 M

Osmolality Viscosity Salt

: 1500 mOsm/kg H2O : 5,2 mPa.s at 37C : Meglumine only

Iodine content : 30 g of iodine / 100 ml

TELEBRIX 30 M
CT
Compared safety of Telebrix 30 M vs Optiray in CT examinations Pr L. LOPEZ & coll.

Objective: compared safety of Tel 30 M vs Optiray 300 Material and methods: - 364 patients included in this randomised double blind study for CT examination (malignant tumors mainly) - average contrast agent volume : 100 ml (30/200 ml) Evaluation criteria: - local safety - overall safety

TELEBRIX 30 M
CT

Results LOCAL SAFETY

TELEBRIX 30 M
CT

Results

OVERALL SAFETY
number of patients Telebrix 30M Optiray 300 no pain at injection site 168 170 92% 93% pain at injection site 14 12 8% 7%

num ber of patients Telebrix 30M O ptiray 300

no nausea 172 177 95% 97% 10 5

nausea 5% 3%

TELEBRIX 30 M
CT
CONCLUSIONS

Sensation of heat higher in the Telebrix group. Telebrix 30 M is more hyperosmolar to plasma than Optiray Global level of AE comparable in both groups Telebrix 30 M allows a rapid, easy and painless injection because of its lack of sodium and its fluidity high level of tolerance recommended in brain CT

TELEBRIX 30 M
Conventional CT

High quality of CT contrast enhancement in vascular and interstitial compartments Good differential diagnosis in the brain, chest and pelvis

TELEBRIX 30 M
Spiral CT

Telebrix 30 M allows a strong enhancement of vessels and high image quality after bolus injection Due to fluidity and adequate iodine content

TELEBRIX 30 M
IVU
Safety of Telebrix 30 M compared to Meglumine Diatrizoate in IVU - Pr K. Rothenberger & coll.

Objective: evaluation of the safety of Tel. 30 M in IVU Material and methods: 260 patients received 50 ml either Tel. 30 M or Diatrizoate Evaluation criteria: safety (adverse events)

TELEBRIX 30 M
IVU

Results
Adverse events warmth nausea pain at injection site vomiting urticaria Telebrix 30M (% of patients) 0.7 2.3 Diatrizoate (% of patients) 6.9 6.2 1.5 2.3 2.3

TELEBRIX 30 M
IVU
CONCLUSIONS

Telebrix 30 M is well tolerated : 97 % of case without AE The image quality was satisfactory in 104 cases The high diffusibility of Telebrix 30 M combined with its hydrophilicity explain these results

SYNTHESIS
product indication CT examinations volume recommended IVU volume recommended IVU (perfusion) volume recommended retrograde cystography volume recommended cerebral arteriography volume recommended phlebography volume recommended YES 2-3ml/kg YES 2-3ml/kg NO YES 100-120ml YES 1-2ml/kg NO YES (chest) 120ml NO YES adult:250ml child: according to age YES 250 to 500ml NO NO Telebrix 35 Telebrix 30M Telebrix 12Na

NO NO YES 80-100ml/leg

NO YES 4-5ml/kg YES 80-100ml/leg

Telebrix range: myelography

absolute contra indication

TELEBRIX range: How supplied?

20ml

30ml

50ml

50ml+ set

100ml

130ml

140ml

150ml

200ml

250ml

TELEBRIX 35 TELEBRIX 30M TELEBRIX 12 Na TELEBRIX HYSTERO

X X

X X

X X X X X

X X X