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Radiotoxicologie, Radiochimie, Radiopharmacie FARM 3200

Cours n° 7

RADIOPHARMACIE (1) Introduction et critères de qualité

Prof. Bernard Gallez

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Radiopharmaceutiques Généralités

Radiopharmaceutique

= préparation pharmaceutique, contenant un ou plusieurs radionucléides, utilisée en médecine humaine ou vétérinaire, pour le diagnostic in vivo ou in vitro, ou pour la thérapie

Cas le plus courant:

nucléide radioactif sous forme non scellée, destiné à l’administration à un patient pour des raisons de diagnostic ou de thérapeutique

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Radiopharmaceutiques Types de préparations

Produits enregistrés prêts à l’emploi

Nucléides contenu dans une formulation « stable »

Produits enregistrés « semi-préparés »

Générateurs

Kits

Produits « maison » (non enregistrés)

Radiopharmaceutiques PET non enregistrés

Anticorps, peptides radiomarqués

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Radiopharmaceutiques Réponse pharmacologique

Les composés doivent être radiomarqués avec une activité spécifique suffisamment haute pour minimiser les possibilités d’effets pharmacologiques

En principe, pas d’effet pharmacologique, sauf émanant d’allergie potentielle à un composant particulier ou modulation pharmacologique de la distribution radiopharmaceutique

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Radiopharmaceutiques Interactions médicamenteuses

Interactions désirées

Utilisation d’un médicament en vue d’induire une réponse pharmacologique qui influence la performance fonctionnelle d’un organe ou d’un tissu, cette performance étant mesurée à l’aide de la biodistribution du radiopharmaceutique

Interactions non-désirées

Modification non voulues des performances d’un radiopharmaceutique par la prise de médicaments

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Radiopharmaceutiques Interactions médicamenteuses

Exemples d’interactions désirées

Perfusion myocardique

Dipyridamole, adénosine, dobutamine

Perfusion cérébrale

Acétazolamide (Diamox)

Etudes rénales

Furosémide, captopril

Etudes hépato-biliaires

Cholecystokinine

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Radiopharmaceutiques Interactions médicamenteuses non désirées

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Radiopharmaceutiques Interactions médicamenteuses non désirées

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Radiopharmaceutiques Interactions médicamenteuses non désirées

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Radiopharmaceutiques Formes des préparations

Solutions vraies

Dispersions colloïdales

Suspension particulaires

Gaz

Aérosols (liquides dispersés en phase gazeuse)

Gélules

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Radiopharmaceutiques Facteurs affectant la Biodistribution

Perfusion

Débit sanguin régional

Perméabilité capillaire

Diffusion à travers membranes biologiques

Taille particulaire

Interactions cellulaires

Transport actif

Transport facilité

Phagocytose

Interactions/biotransformations intracellulaires

Elimination

Rénale

Bile

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Quality control parameters

Radioactivity tests - radioativity

- identification of the nuclide

- radionuclidic purity

- radiochemical purity

- specific radioactivity

Specific tests for some radiopharmaceuticals - Physiological distribution

Usual tests for injectable solutions

- chemical purity

- sterility

- apyrogenicity

- pH

- isotonicity

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Quality criteria Radioactivity

Definition : radioactivity of a preparation = number of nuclear desintegrations or transformations per unit time.

Units (International System) : Becquerel (Bq) = 1 nuclear transformation per second

1 Ci = 3.7 1010 Bq = 37 GBq

1 mCi = 3.7 107 Bq = 37 MBq

1µCi = 3.7 104 Bq = 37 kBq

1 GBq = 27.027 mCi

1 MBq = 27.027 µCi

1 kBq = 27.027 nCi

Absolute radioactivity measurements require a specialized laboratory but identification and measurement of radiation can be carried out comparatively and relatively by the use of radioactive standards.

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Quality criteria Radioactivity

The absolute measurement of radioactivity of a given sample may be carried out if the decay scheme of the radionuclide is known, but in practice many corrections are required to obtain accurate results.

It is common to carry out the measurement with the aid of primary standard source.

Primary standards may not be available for short-lived radiopharmaceuticals.

For these radionuclides, the instruments may be calibrated using a secondary standard (e.g. 57Co (T=270 days) can be used as secondary standard for 99mTc).

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Counters

- Ionisation chambers and Geiger-Müller counters

> beta/gamma emitters

- Solid scintillators or semiconductor counters

> gamma emitters

- Liquid-scintillation counters

> low-energy beta emitters

Whatever apparatus is used, for an accurate comparison of radioactive sources, it is essential for samples to be measured under identical conditions.

Quality criteria Radioactivity

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Quality criteria Radioactivity / Specific problems

Quenching in liquid scintillation Measurements should be corrected for light- quenching effects

Internal standardization

External standardization

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Quality criteria Radioactivity / Specific problems

Background

All measurements of radioactivity should be corrected by substracting the background activity due to radioactivity in the environment and to spurious signals generated in the equipment itself

Dead time of counters

When measurements are made at high levels of radioactivity, it may be necesary to correct for the finite resolving time of the detector

Calibrations

The following factors should be taken into account:

Calibration factor

Sample geometry factor

Dynamic range accuracy

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Quality criteria Radioactivity

Statistics in counting

The results of determinations of radioactivity shows variations which mainly derive from the random nature of nuclear transformations. A sufficient number of counts should be registered in order to compensate for variations in the number of transformations per unit of time. The standard deviation is the square root of the counts, so at least 10000 counts are necessary to obtain a relative standard deviation of not more than 1 per cent.

Reference to a time

All statements of radioactive content should be accompanied by a statement of the date and the time at which the measurment was made (and reference to a time zone if exported)

The radioactivity of a solution is expressed per unit volume to give the radioactive concentration

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Quality criteria Identification of the radionuclide

The radionuclide is identified by:

Measuring the half-life of the radionuclide

and/or

Determining the nature and energy of the radiation

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Quality criteria Identification of the radionuclide Half-life Radioactive decay

Radioactivity decays at an exponential rate which is characteristic for each radionuclide

The curve of exponential decay is described by the equation:

At = Ao.e-λt

At = the radioactivity at time t

Ao = the radioactivity at time = 0

λ = the decay constant characteristic of each radionuclide

E = the base of Napierian logarithms

o Half-life

The time in which a given quantity of radionuclide decays to half its initial value.

The half-life (T1/2) is related to the decay constant (λ) by the equation:

T1/2 = ln 2 / λ (ln 2 = 0.693)

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The half-life is measured with a suitable detection apparatus. The radioactivity chosen, having regard to experimental conditions, must be sufficiently high to allow detection during several presumed half-lives, but should be limited to minimize count rate defects and effects such as dead time losses.

The same source is measured in the same geometrical conditions at intervals usually corresponding to half of the half-life throughout a time equal to about three half-lives.

A graph is drawn with time as the abcissa and the logarithm of the instrument response as the ordinate.

The calculated half-life should not differ by more than 5 per cent from the half-life stated in the pharmacopeia.

Quality criteria Identification of the radionuclide Half-life

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The nature and energy of the radiation emitted may be determined by several procedures including the construction of an attenuation curve and the use of spectrometry

The attenuation curve is often used for analysis of β- radiation

Liquid scintillation counting and spectrometry can be used for α and β- emitters

γ spectrometry is used to identify radionuclides with gamma rays and detectable X-Rays.

Quality criteria Identification of the radionuclide Nature and energy of radiations

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Attenuation curve

The attenuation curve is dra