Nuclear Pharmacy. Jim Velez Director, Nuclear Pharmacy (206) (206) Pager

Transcription

1 Jim Velez Director, Nuclear Pharmacy (206) (206) Pager 1

2 Chapter One Radiopharmaceuticals 1

3 Radionuclides, Radiochemicals & Radiopharmaceuticals Carrier-free (stable atoms) Specific Activity (mci/mg) 1

4 Design Characteristics of Radiopharmaceuticals Decay should result in gamma emissions of (l kev) Sufficient abundance of emissions for detection. Should NOT contain particulate radiation (beta emissions), Increases patient's radiation dose & degrades diagnostic info Beta emissions are therapeutic Effective half-life long enough for the intended study Specific activity should be high Pharmaceutical component should be: non toxic Free of secondary effects. 1

5 Design Characteristics of Radiopharmaceuticals Radiopharmaceutical should not disassociate in vitro or in vivo, Should be readily available or easily compounded Should have a reasonable cost. Should rapidly and specifically localize according to the intended application Background clearance should be rapid good target-to-background ratios 1

6 Radionuclide Production Naturally occurring radionuclides have half-lives (>1000 years) and are heavy & toxic most common clinical Radionuclides are artificially produced Reactor Produced radionuclides I-131, Xe-133, Cr-51 & Mo-99 Cyclotron/Accelerator Produced radionuclides: I-123, Tl-201, Ga-67, In-111 & F-18 See table 1-2 1

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8 Mo-99/Tc-99m Generators Provides easy access to short-lived radionuclides Consist of a longer-lived parent and a shorter-lived daughter Mo-99/Tc-99m generator is the most common system Mo-99 is fission produced (fission of U-235) Wet vs. Dry radionuclide generator Maximum Tc-99m ingrowth occurs in 23 hrs (20-30 hrs) Tc-99m on column decays to Tc-99 (stable) becomes carrier Tc-99 competes with Tc-99m for tagging sites on chelates Elution is Pertechnetate (TcO 4- ), valence state +7 Pertechnetate must be reduced to tag with kits 1

9 Mo-99 /Tc-99m Generator Quality Control Radionuclidic Purity Chemical Purity Radiochemical Purity 1

10 Radionuclidic Purity Mo-99 is the most common radionuclidic contaminant in an elution Tc-99 (decayed Tc-99m) can be problematic Tc-99 half-life is 2.1 x 10 5 years virtually stable The NRC limit is 0.15 uci Mo-99 per mci of Tc-99m Chemical Purity The presence of Alumina in the eluate (from column) Maximum alumina concentration is 10µg/ml Colorometric test Alumina interferes with normal radiopharmaceutical distribution 1

11 Radiochemical Purity TcO - 4 Pertechnetate valence is +7 USP standard is 95% Tc-99m Reduced forms valences +6, +5, +4 are impurities Are detected by TLC Increased radiochemical impurities will cuase poor kit tagging 1

12 Technetium Chemistry Tc-99m must be reduced from valence +7 for chelation Reduction is accomplished using Stannous Chloride Except Sulfur Colloid Final oxidation state of Tc-99m is unknown or debated Due to multi-positional tagging of chelate 1

13 Commercial Kit Formulations Commercial kits contain: Reaction vial - non-radioactive pharmaceutical Stannous chloride - buffering agent Stabilizing agents - N 2 purged* *excess O 2 will react with stannous chloride resulting in Free pertechnetate Radiolysis will also result in free pertechnatate formation 1

14 QA of Tc-99m Radiopharmaceuticals Radiochemical Purity the percentage of the total radioactivity in a specimen that is in the desired radiochemical form Each radiopharmaceutical has a specific radiochemical purity to meet USP/FDA requirements, typically 90% Causes of radiochemical impurities are: Poor labeling efficiency - Radiolysis Decomposition - ph changes Oxidizing/reducing agents - Exposure to light

15 Radiochemical impurities contribute to: Background activity Degraded image quality Altered biodistribution Radiochemical purity is assayed using Thin Layer Chromatography (TLC) Tc-99m Radiopharmaceuticals are tested for the following impurities: Free pertechnetate -Reduced hydrolyzed

16 Radiopharmaceutical TLC TLC systems exist for each Tc-99m agent Two strip methodology allows measurement of all three components of a radiopharmaceutical TLC Strips can be cut and counted or scanned TLC Pitfalls Inadvertently immersion of the sample spot spots are not allowed to dry when using organic solvents excessive delay in starting the TLC

17 Radioiodine I-131 First radiopharmaceutical of importance: Thyroid A number of radiolabeled agents: Hippuran - Human Serum Albumin (HAS) MIBG - Macroaggregated Albumin (MAA) I-131 Disadvantages: High photon energy (364 kev) Long half-life (8 days) Beta particle emission Currently the treatment of choice for hyperthyroidism and differentiated thyroid cancer

18 Radioiodine I-123 Essentially replaced I-131 for Dx use I-123 Advantages: Good photon energy (159 kev) Shorter half-life (13.2 hrs) Electron capture decay ( patient dose) improved target-to-background ratio Newer applications include: I-123 MIBG I-123 DATScan

19 Indium In-111 A versatile Radiometal for Dx use photon energies of 172 kev & 245 kev Half-life of 2.8 days permits multiple-day sequential imaging Current In-111 agents include: In-111 oxine leukocytes In-111 OctreoScan In-111 ProstaScint Used extensively in mab radiolabeling

20 Gallium Ga-67 Citrate Localizes in tumors and inflammatory conditions Transported and extracted like iron Ga-67 Diadvanatages: multiple photopeaks, most abundant is lowest energy Clinically, only photopeaks (93 kev;185 kev; 300 kev) are acquired Higher energies scatter degrades the image slow clearance necessitates delayed imaging: 48 & 72 hr Early kidney & delayed bowel excretion complicates abdomen imaging Laxatives may be required to clear obscuring activity

21 Thallium Tl-201 Radiopharmaceutical for myocardial imaging A potassium analog, with high clearance (~85%) excellent marker of regional blood flow to viable myocardium Disadvantage, lacks ideal photopeak Gammas of rays at 135 & 167 kev occur in low abundance acquire characteristic x-rays, range of kev Due to poor imaging characteristics, alternative Tc-99m radiopharmaceuticals are now available

22 Radioactive Inert Gases (no longer used) Gases for pulmonary ventilation imaging Xenon Xe-133 (poor imaging) Low imaging energy 81 KeV Half-life is 5.2 days Xenon Xe-127 (costly to produce) High imaging energy 172 & 203 kev Half-life is 36.4 days Krypton Kr-81m (generator system) (costly to produce) High imaging energy gamma 190 kev Half-life is 13 seconds All vent studies essentially replaced by Tc-99m DTPA

23 PET Radiopharmaceuticals Carbon C-ll, Nitrogen N-13, or Oxygen 0-15 Fluorine F-18 has the advantage of a longer half-life, 110 minutes Requires Cyclotron/F-18 commercially available F-18 FDG is a glucose analog a marker of tumor metabolism and viability wide application in wholebody tumor imaging With some brain and cardiac applicability

24 Rubidium Rb-82 Generator System: Sr-82/Rb-82 Rb-82 is a potassium analog for myocardial perfusion imaging (like Tl-201) High energy positron emission MeV High energy degrades the spatial resolution

25 Radiopharmaceutical Dispensing Requires general laboratory & radiation safety protocols Regulated by FDA, NRC/AS, state BOP, hospital radiation safety committees Radiopharms are prescriptions requiring they be ordered and administered by an authorized individual (AU) A good standard of practice, QC should always be performed Administered activity should be: within ±10% of the prescription request for Dx agents within ±20% of the prescription request for Tx agents

26 Pregnancy Possibility of pregnancy should be considered for every childbearing age woman risk-to-benefit ratio must be considered for pregnant women Radiation dosage should be minimized Employ radpharms that do not cross the placenta Tc-99m does not cross placenta Iodine does cross placenta, fetus concentrates iodine at weeks

27 Lactation Breastfeeding suspension is determined by: the halflife of the radionuclide the degree to which it is secreted in breast milk I-131 is secreted and breastfeeding should be terminated altogether I-123, it is recommended that breastfeeding could safely resume after 2-3 days For Tc-99m agents, hours is sufficient See Table 1-11 for specific guidance

28 Pediatric Dosage Selection There are several methods for scaling down the amount of radioactivity administered to children BSA correlates better than body weight for dosage calculation (BSA table) Each site selects a method and standardizes its application Calculated dose may not always be adequate to obtain diagnostically useful data and physician judgment must be used

29 A calculation based on body weight: Ped dose=patient weight (kg) / 70 kg x Adult dose Webster's rule* (alternative calculation): Ped dose=age+1 / Age+7 x Adult Dose * This formula is not appropriate for infants

30 Medical Event Definition a radiopharmaceutical dose administration involving the wrong patient, wrong radiopharmaceutical, wrong route of administration, or an administered dose differing from the prescribed dose when the effective dose equivalent to the Patient exceeds 5 rem to the whole body or 50 rem to any individual organ

31 Medical Event (Misadministration) Definition and procedures for handling radiopharmaceutical Medical Events are set out in the 10 CFR-Part 35 As defined, Medical Events are unlikely to occur for Dx NM procedures Most Medical Events will likely result from Tx procedures (I-131, Y-90, etc.) Medical Events have specific reporting and notification requirements Complete records must be retained and available for NRC/AS review for 10 yrs.

32 Annual Dose Limits for Radiation Exposure Adult Occupational 5 rem (0.05 Sv) total effective dose equivalent 50 rem (0.5 Sv) to any organ, tissue, extremity 15 rem (0.15 Sv) to the lens of the eye Minors (<18 y.o.) Occupational 10% of those for adult workers Embryo/Fetus Occupational 0.5 rem (5 msv) during gestation period

33 Annual Dose Limits for Radiation Exposure The dose limit to non-radiation workers and members of the public are two percent of the annual occupational dose limit. Members of the Public (Non-occupational) 0.1 rem (1 msv) whole body dose 2 mrem (0.02 msv) in any hour (average)

34 NRC vs. Agreement State Individual states have agreements with NRC granting them authority to license and inspect by-product, source, or special nuclear material NRC only governs reactor-produced RAM States must govern cyclotron-produced RAM Individual states, not the NRC, regulate the use of positron emission tomography

35 Adverse Rxns to Diagnostic Radpharms Adverse reactions to radpharms are less common than adverse reactions to iodinated contrast media Reactions are usually mild and rarely fatal The greatest concern is of allergic reactions for: agents containing human serum albumin The gelatin in Sulfur Colloid Preps (animal protein) antibody imaging agents causing human anti-mouse antibodies (HAMA) reactions developed after repeated exposure to radiolabeled MAbs * Tc-99m NeutroSpec is no longer marketed

36 Radiation Accidents (spills) Spills are divided into minor and major categories depending on radionuclide and amount spilled For I-131, < 1mCi is minor, > 1mCi major For Tc-99m, > 100mCi is major, all else minor Principles of responding to both kinds of spills is essentially the same

37 Minor Spills Warn people that a spill has occurred Attempt to prevent the spread material Cover the spill, make it visibly identifiable Clean up immediately using appropriate technique Use soap and water, disposable gloves, and remote handling devices Dispose of in designated bags Continually survey with a G-M meter until the reading is at background levels Monitor personnel involved hands, shoes, and clothing Report to RSO

38 Major Spills Clear area immediately to contain spread Seal off room and notify RSO immediately RSO typically directs the response including: determination of when and how to proceed with cleanup and decontamination At all times the main intent is to keep radiation exposure of patients, hospital staff, and the environment to a minimum

39 Quality Control in Nuclear Medicine In additional other quality control procedures, nuclear pharmacies ensure sterility and apyrogenicity of administered radiopharmaceuticals Sterility and Pyrogen Testing Sterility implies the absence of living organisms Apyrogenicity implies the absence of metabolic products such as endotoxins

40 Sterility and Pyrogen Testing As radiopharmaceuticals are prepared just prior to use, definitive testing before administration is impractical, which doubles the need for careful aseptic technique Methods of sterilization: Autoclaving -is not useful for radpharms Terminal sterilization utilizes membrane filtration filter pore size of 0.22 µm is necessary to sterilize a solution 0.22 µm filter traps bacteria and small organisms such as Pseudomonas

41 Sterility and Pyrogen Testing Sterility test standards are defined by the USP Thioglycollate and soybean casein digest media are used for the different categories of microorganisms, including anaerobic and aerobic bacteria, and fungi

42 Pyrogens are protein or polysaccharide metabolites of microorganisms that cause febrile reactions Pyrogens can even be present in sterile preps The clinical syndrome is fever, chills, joint pain, and headache developed minutes to a few hours post injection The pyrogenic reaction lasts several hours and alone is non-fatal

43 Pyrogen Testing Testing criteria established by USP Historical method sample injected into rabbits and temp response monitored current USP test methodology uses Limulus Amebocyte Lysate (LAL) Test Amebocyte lysate prepared from horseshoe crab blood Preps become opaque/gels in the presence of pyrogens

44 Radiopharmaceutical Dose Calibrators Dose calibrators are subject to four quality control requirements: Accuracy Linearity Precision or constancy geometry

45 Accuracy Assessed using NIST traceable reference standard sources The test is performed annually Two different sources are used The measured activity from the standard Cannot vary more than 10% If greater or less than 10% device must be recalibrated.

46 Linearity Test designed to determine the response of the calibrator over a range of activities Assessed by measuring Tc-99m sample sequentially during radioactive decay any deviation in assay value indicates equipment malfunction and nonlinearity Alternate method uses pre-calibrated lead attenuators with sequential measurements This test is performed quarterly

47 Precision or Constancy Test is designed to measure the ability of the dose calibrator to repeatedly measure the same specimen over time A long-lived standard is used Barium-133 (356 kev, Tl/ years Cesium-137 (662 kev, Tl/2 30 years Cobalt-57 (122 kev, T1/2 271 days The test is performed daily Observed values should be within 10% of the value for the reference standard.

48 Geometry This test is performed during acceptance testing of the dose calibrator Assesses the calibrator s ability to read the same amount of radioactivity contained in different volumes of sample Readings varying more than 10% from one volume to another, require correction factors are calculated Factors are based on the most commonly measured volume of material determined from dayto-day clinical use

49 Radiation Dosimetry Patient exposure to radiation limits the amount of radioactivity that can be administered An exact radiation dose cannot be calculated For radpharms estimates of radiation absorbed doses are part of the drug approval process may be taken as "average levels of exposure Radiation absorbed dose to any organ depends on: biological factors (% uptake, biological T½) physical factors (amount & nature of emitted radiations

50 Radiation Dosimetry Radiation doses are typically given in rads (radiation absorbed dose) One rad is equal to the absorption of 100 ergs per gram of tissue The total absorbed dose to a region or organ is the sum of the contributions from all source regions around it and from activity within the target organ itself

51 Radiation Dosimetry Factors affecting the patient specific dosimetry include: the amount of activity administered originally the biodistribution in a given patient vs. another the route of administration the rate of elimination the size of the patient the presence of pathological processes

52 Questions???