Radiofarmaca basisbegrippen VZA 1/10/2019€¦ · GC pH Half-life Conditional release Post-release...

Radiofarmaca

basisbegrippen

VZA 1/10/2019

Guy Bormans

Radiofarmaceutische Research KU Leuven www.radiopharmacy.be

Wetgeving

KB 4/3/1991 normen ziekenhuisapotheek

Art.9 opdrachten ziekenhuisapotheker :

9° Het toezicht houden op de galenische bereiding van inspuitbare radiofarmaceutische

preparaten.

KB 20/7/2001 algemeen reglement op de bescherming van de bevolking, van de

werknemers en het leefmilieu tegen het gevaar van de ioniserende stralingen (ARBIS)

Art 54.8.2. Verplichtingen inzake bescherming en toezicht

De persoon die vergund is om radionucliden in bezit te houden en te gebruiken:

f. treft de nodige maatregelen om de toegang tot de lokalen en een doeltreffende

bescherming in de zin van artikel 2 te verzekeren voor de persoon belast met de

uitoefening van het toezicht op de galenische bereiding van inspuitbare radio-farmaceutische

bereidingen, overeenkomstig het koninklijk besluit van 4 maart 1991

houdende vaststelling van de normen waaraan een ziekenhuisapotheek moet voldoen om te

worden erkend.

201?

Nieuw KB ziekenhuisapotheken gebaseerd op PICs guide: ?

radioisotopes

#protons

#neutrons

p=n

P+N>>>

fission/a emission

Proton excess

p+n+e

+ + v (

+-decay)

918

818F O

p++e

-n+ v (electron capture)

81201

80201Tl Hg

Neutron excess np

++e

-+v

53131

54131I Xe

Isomeric transition

From excited state to ground state= 99mTc 99Tc + γ (140 keV)

Type of radiation

Particulate radiation:

a-radiation: 2p + 2n (He-nucleus)

--radiation: electrons

+-radiation: positrons

neutrons

electromagnetic radiation:

X-rays, -rays

High LET

(linear energy transfer)

Strong cel damage

Can not be detected externally

THERAPY

Low LET

Relatively low cel damage

Can be detected externally

only pmol radionuclide required

Tissue is transparent for X/γ

IMAGING

The body is transparant for gamma radiation

Radionuclides can be “tracked” in the body by

external detection of gamma radiation

SPECT single photon emission

tomography

PET positron emission tomography

Image contrast depends on local

concentration of the radionuclide

amounts of radionuclides for medical use

A=N*λ

Typical nanogram (10-9 g) range

No pharmacologic side effects (“tracer principle”)

Sometimes side effects from additives and precursors

Radiopharmacological side effects are possible (longlived beta or gamma-emitters)

Polonium-210 colloid (a-straler)

Concentrates in liver and spleen

Lethale dose (oral) : 50 ng

Not detectable externally

Alexander Litvinenko

Radiopharmaceuticals

Vector molecule:

Specific molecular interaction

(receptor, transporter, enzyme,…):

Responsible for imaging contrast

for molecular imaging (diagnosis)

Radionuclide:

Emits upon decay externally

detectable gamma or X rays

Vectormolecule:Radionuclide:

Emits upon decay particulate

radiation fordestruction of

target cells

Radiopharmaceuticalsfor therapy

Specific molecular interaction

(receptor, transporter, enzyme,…)

Responisble for irradiation selectivity

vector

Vectorisation of radiopharmaceuticals

•Installation in specific compartment

•Gas inhalation (lung ventilation)

•Radioactive food and drink (stomach evacuation)

•Substrate for transporter system

•Physical transport (eg glomerular filtration kidney)

•Molecular transport (eg NaI (NIS symporter; organic anion

transporter (liver); tubular secretion (kidney);

neurotransmitter transporters (e.g. dopamine transporter)

vector

•(pseudo)-irreversible trapping

• Physical trapping in capillaries (99mTc-macroaggregates)

• Colloidal particles by the RES

• Metabolic fixation/substrate for enzyme and trapping of

reaction product

• Alkylation of biomolecule (covalent binding)

•Equilibrium binding

•Immunological interaction (labelled antibodies)

•receptor interaction

Choice of radionuclideDiagnosis Therapy

decay IT, electron capture,

β+

β-, a, EC

Halflife 1-24h-4d 3-20 d

Gamma-energy 100-200 keV (511

keV PET)

Cost

availability Cyclotron,

generator (99mTc; 68Ga)

Nuclear reactor,

generator

Chemistry Efficiënt and fast conjugation to vector

molecules, without changing the

biologic characteristics of the vector

Radionuclides for imaging

12

Radio-

nuclide

Half-

life

Mode

of

decay

β+

Emax

(keV)

range

in H2O

(mm)

Chemistry production CNS

tracers

antibodies peptides

13N 9.97 min β+ (100%) 1198 keV

5.1 mm

Very fast

organic

chemistry

Cyclotron

Liquid target16O (p,α)

11C 20.4 min β+ (100%) 960 keV

3.9 mm

Fast organic

chemistry

Cyclotron

Gas target14N(p,α)

68Ga 68 min β+ (89%)

EC (11%)

1899 keV

8.9 mm

Chelation

chemistry

Generator68Ge-68Ga

18F 109.8

min

β+ (97%)

EC (3%)

634 keV

2.3 mm

Fast organic

chemistry

Cyclotron

Liquid target18O(p,n)

89Zr 78.4 h β+ (100%) 897 keV

3.6 mm

Chelation

chemistry

Cyclotron

Solid trarget89Y(p,n)

124I 4.17 d β+ (23%)

EC (77%)

1535

keV(50%)

6.9 mm

2138 keV

(50%)

10.2 mm

Organic

chemistry

Cyclotron

Solid target124Te(p,n)

99mTc 6h Isomeric

transition

n/a Chelation

chemistry

(reduction of Tc

required)

generator

Radiopharmaceutical Research13

Production of radiopharmaceutical

Production of radionuclide

cyclotron

generator

Nuclear reactor

Incorporation of radionuclide in target molecule

(conjugation to the vector)Chelation (complexation)

Fast, efficient, aqueous solution

Not for small molecules

Organic chemistry

Organic solvents, purification

Not for biologicals

QC

Radionuclides for imaging

14

Radio-

nuclide

Half-

life

Mode

of

decay

β+

Emax

(keV)

range

in H2O

(mm)

Chemistry production CNS

tracers

antibodies peptides

13N 9.97 min β+ (100%) 1198 keV

5.1 mm

Very fast

organic

chemistry

Cyclotron

Liquid target16O (p,α)

11C 20.4 min β+ (100%) 960 keV

3.9 mm

Fast organic

chemistry

Cyclotron

Gas target14N(p,α)

68Ga 68 min β+ (89%)

EC (11%)

1899 keV

8.9 mm

Chelation

chemistry

Generator68Ge-68Ga

18F 109.8

min

β+ (97%)

EC (3%)

634 keV

2.3 mm

Fast organic

chemistry

Cyclotron

Liquid target18O(p,n)

89Zr 78.4 h β+ (100%) 897 keV

3.6 mm

Chelation

chemistry

Cyclotron

Solid trarget89Y(p,n)

124I 4.17 d β+ (23%)

EC (77%)

1535

keV(50%)

6.9 mm

2138 keV

(50%)

10.2 mm

Organic

chemistry

Cyclotron

Solid target124Te(p,n)

99mTc 6h Isomeric

transition

n/a Chelation

chemistry

(reduction of Tc

required)

generator

Radionuclides for radionuclide therapy: β- emitters

15

Radionuclides for radionuclide therapy: α emitters

16

Radionuclide generator

• Dochternuclide van langerlevend moedernuclide is zelf radioactief

• Bij verval moedernuclide wordt dochternuclide aangemaakt

• Scheiding van dochternuclide en moedernuclide (blijft in de generator)

Radionuclide generator:

langerlevend moedernuclide vervalt naar dochternuclide

99Mo 99mTc

-

42 43

IT99Tc43

t

ln(activiteit)

t

ln(activiteit)

Scheiding van dochter en moedernuclide

Elutie van de generatorkolom:

Dochternuclide wordt van de generator geëlueerd

Moedernuclide blijft op de kolom

99Mo 99mTc

-

42 43

IT99Tc43

Ingroei van dochternuclide door verval moedernuclide

t

99Mo 99mTc

-

42 43

IT99Tc43


Radiopharmaceuticals: classificationPreparation• Ready for use

• (Kit) preparation99mTc-radiopharmaceuticals68Ga-radiopharmaceuticals

Addition of (registered) generator eluate to

(registered) labelling kit

(similar to reconstitituion of antibiotic)

LAF hood

Simple QC

• manufacteringPET-radiopharmaceuticals (18F/11C)

Extensive “organic chemistry” synthesis procedure

synthesis module including preparative HPLC

hotcells- clean room

Extensive QC/need for radiopharmacist

+


QC of radiopharmaceuticals

-chemical purity: (non-radioactive) chemical impuritues

-radiochemical purity: desired radionuclide in undesired chemical form

-radionuclidical purity: undesired radionuclide

-microbiological purity: bacteria, molds, endotoxins,…



-chemical purity

99mTc-radiopharmaceuticals: kit labeling

Chemical purity labeling kit is responsibility of the

manufacterer of cold kits and generator

3.15 mg oxidronate sodium

0.26 mg, SnCl2 (reducing agent)

0.84 mg gentisic acid (stabilizer)

30.0 mg sodium chloride

+ 99mTcO4-

10 µg 99mTc-oxidronate





Chemical composition labeling kit

(almost) doesn’t change

99Mo-99mTc

generator



-radiochemical purity


Technetium-99m in an undesired chemical form

(99mTcO4- , 99mTcO2)





+ 99mTcO4-






99mTcO2

Count

activity

99mTcO2

99mTc-oxidronate

+ 99mTcO4-

(quantitative)

1000 fold higher amount of

chelator compared to 99mTc

labelled radiopharmaceutical



-radionuclidical purity

99mTc-radiopharmaceuticals: kit labeling99Mo breakthrough from the generator99Mo halflife = 66h, β- emitter

(high radiation dose)

+ 99mTcO4-


? 99MoO42-

+ 99MoO42-Gamma spectrometry

Dose calibrator



-microbiological purity


Sterile generator

GMP producedSterile kit

GMP produced

Aseptic reconstitution

Aseptic dose fractionation

(multidose vial)

Sterility test (can also be used for media fills)

endotoxin test

27


-chemical purityPET-radiopharmaceuticals: organic synthesis

Chemical purity is responsibility of the PET production centre

CH3CN

NaOH

Organic solvent: gas chromatography

Strong base: pHNasty reagent: TLC, HPLC18O(p,n)18F

18FDG

2-[18F]fluoro-2-deoxy-D-glucose

28


-chemical purity

Radioactivity detection

mass detection

18FDG

[18F]fluoro-2-deoxy-D-glucose

Molar activity: amount of nmol/Bq

FDG

[18+19F]fluoro-2-deoxy-D-glucose

Usually ng

Usually µg

1000-fold

“contamination”!

PET-radiopharmaceuticals: organic synthesis

PET radiopharmaceutical can be “contaminated” by stable

isotope homologue

29


-radiochemical purityPET-radiopharmaceuticals: organic synthesis

radiochemical purity is responsibility of the PET production

centre

CH3CN

NaOH

18F-fluoride that did not react:TLC/HPLC18O(p,n)18FIncomplete hydrolysis Ac-18FDG (TLC/HPLC)

Racemisation:18FD mannose (HPLC)

radioHPLC: identification, chemical and radiochemical purity

30


-radionuclidical purity


radionuclidical purity is responsibility of the PET production

centre, but usually not a problem since PET tracers are HPLC

purified18O(p,n)18F

Nuclear side reactions

Long lived radionuclides from activation

of target foils

Gamma spectrometry

31


-microbiological purity


Microbioogical purity is responsibility of the PET production

centre

Low bioburden: sterile disposible

cassettes for radiosynthesis

Class C room

Class C

Hotcell

Radiosynthesis

Class B passbox Class A passbox

Class A dispensing cell

Sterile filtration and dispensing

32

QC of radiopharmaceuticalsPET-radiopharmaceuticals: organic synthesis

Microbioogical purity is responsibility of the PET production

centre

Class C room

Class C

Hotcell

Radiosynthesis

Class B passbox Class A passbox




Release flow PET (t)racer

ProductionCyclotron

production

Radiosynthesis

HPLC purification

Filtration and

formulation

Pre-release QC

HPLC

TLC

GC

pH

Half-life

Conditional

release

Post-release QC

Sterility

endotoxins

Longlived

radionuclides

Patient

injection

0.5-1h +20 min

Final

release

+14 days

• They make only nanograms of “active” ingredient costing >100 M€/mg

• They can only use their pharmaceuticals for a couple of hours

• Their active ingredients are usually contaminated with a thousand-fold stable

isotope homologue or chelator


The worlds worst pharmacists are radiopharmacists

Worlds worst

pharmacist


Protection of radiopharmaceutical against environment

Biohazard vertical flow

LAF hood

Class C/D environment

99mTc-radiopharmaceuticals



Class C room

Class C

Hotcell

Radiosynthesis

underpressure

Class B passbox

overpressure

Class A passbox

overpressure



overpressure

18F/11C-radiopharmaceuticals


Pressure hill:

Avoids microbiologically

contaminated air from getting in

Avoids radioactively

contaminated air from getting out


Protection of environment against radiopharmaceutical

2 risks:

1. (airborne) contamination: underpressure

2. Irradiation: shielding (Pb)



Biohazard vertical flow

LAF hood:

underpressure Lead/Leadglass shielding

10 mm Pb

99mTc-radiopharmaceuticals


Class C room

Class C

Hotcell

Radiosynthesis

underpressure

Class B passbox

overpressure

Class A passbox

overpressure



overpressure

18F/11C-radiopharmaceuticals


Shielding

7.5-10 cm Pb

Pressure hill:

Avoids microbiologically

contaminated air from getting in

Avoids radioactively

contaminated air from getting out


Protection of environment against radiopharmaceutical:

shielding


Radionuclide therapy isolation room

Protection of environment

against radiation and contamination

Specific risks of radiopharmaceuticalsApplication

• Diagnosis

• Therapy

Highest risk is associated with I.V. injection, microbiological contamination

Altered distribution (radiochemical purity, misadministration,…) can be lethal

Polonium-210 colloid (a-emitter)

Concentrates in liver and spleen

Lethale dose (oral) : 50 ng

Not detectable externally

Alexander Litvinenko

Role of hospital pharmacist-no need to be a theoretical physicist!

• aseptic techniques : provide training (e.g. periodic media fill) and follow-up (similar to chemotherapy

preparation)

• check protocols (full traceability)

Specific risks of radiopharmaceuticals

Key instrument: dose calibrator

• measures the activity (Becquerel) in vials & syringes

• Usually integrated in LAF hood

• the “scale” for radiopharmaceuticals

• should be checked daily (calibration source)

The future of radiopharmaceuticals

Thanks for your attention!

Radiofarmaca basisbegrippen VZA 1/10/2019€¦ · GC pH Half-life Conditional release Post-release...

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