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Radiation dose calculations: from rats to humans E.ERDOCIAIN and Jo.Simiand

Radiation dose calculations: from rats to humans E.ERDOCIAIN and Jo.Simiand Sanofi~Synthelabo Recherche, 195 route d’Espagne, 31036 Toulouse Cedex, France. Radiation dose calculations: from rats to humans.

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Radiation dose calculations: from rats to humans E.ERDOCIAIN and Jo.Simiand

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  1. Radiation dose calculations: from rats to humans E.ERDOCIAIN and Jo.Simiand Sanofi~Synthelabo Recherche, 195 route d’Espagne, 31036 Toulouse Cedex, France

  2. Radiation dose calculations: from rats to humans • Radiolabelled studies in man must first be approved by ARSAC(Advisory of Radioactive Substance Administration Committee) for UK or RDRC (Radioactive Drug Research Committee) for US • Directives and guidelines • WHO Directives (Technical report series 611, Genève, 1977) • Dose absorbed (µSv or mSv) • Number of volunteers • Age of volunteers ( >40 even >50) • Recommendations of the International Commission on Radiological Protection (ICRP publication 60, Pergamon, 1991) • International Commission on Radiation Units and Measurements (ICRU Report 32, Washington, 1979)

  3. Radiation dose calculations: from rats to humans • Category of risks and levels of benefit • As a general rule, the use of the radiolabelled compound should comply with the principles of ALARA (As Low As Reasonnably Acceptable) and should keep the volunteers within Risk Categories I and IIa

  4. Radiation dose calculations: from rats to humans • Biologic effects of ionising radiations and potential risks (OMS 611) • Harmful effects linked to energy of radiation of the isotope • Molecular and structural modifications in tissues • Absorbed dose • Corresponding to the total amount of radiation received by the volunteer • Somatic effects • Genetics effects on germinal cells • Consequences for children born just after irradiation • Consequences for future generations • Rapid decrease of the effects for man > 40 years

  5. Radiation dose calculations: from rats to humans • Purposes • The estimation of the Effective Dose (D; µSv) to individual human tissues by extrapolation from animal data • Estimation of the Committed Effective Dose (CED; µSv) to a typical human subject (70 kg), using supplied weighings to correct for the different sensitivities to damage of the different tissues

  6. Radiation dose calculations: from rats to humans Calculation Approach

  7. Radiation dose calculations: from rats to humans • Required data • Animal tissue distribution • Normally rats (albinos and /or pigmented ) • During a 0 to 336 hours sampling period • Radioactive concentrations expressed as % of dose • Data for eyes and skin must be obtained from a pigmented strain • Excretion balance • Also using rats (albinos) • Urinary and faecal excretion expressed as % (corrected to 100% recovery)

  8. Radiation dose calculations: from rats to humans • Calculation of % dose in tissues of each animal • Tissue weight can be determined using: • Actual weight • Weight derived from nominal weight list in rat (g/kg) • Ideally rats should be weighed at kill time (330 g at day 14 vs 200 g at day 0)

  9. Radiation dose calculations: from rats to humans • Increase of the body weight (g) as function of the age (days) • At day 0: rat weights 200 g • At day 14:rat weight 330 g (+65%) • Increase of body weight • Increase of the % of Dose • Increase of D and CED • Maximization of the risks • Decrease of the radioactive dose to be • administered Day 14 Day 0

  10. Radiation dose calculations: from rats to humans • How can we determine the weight of each tissue or organ • Using Quantitative Whole Body Radioluminography • Tissue weight can not be assessed directly from sections • Tissue weight = relative weight x body weight at the death time

  11. Radiation dose calculations: from rats to humans • How can we determine the weight of each tissue or organ (cont'd) • Using Liquid Scintillation Counting • Weight used corresponds as often as possible to weight observed • Exception for blood • Exceptions for small organs as: • Adrenal gland, thyroïd gland and hypophysis • Exception for diffuse, large or "with problem sampling"organs as: • Prostate, brown and white fats, thymus, • Muscle, pigmented and not pigmented skin • Bone, bone marrow and oesophagus • Weight used is calculated using the same approach than for QWBRLG

  12. Radiation dose calculations: from rats to humans • Calculation of the mean percentage of dose • For PK, values < LOQ would be set to zero • For Dosimetry, values < LOQ are set to the LOQ

  13. Radiation dose calculations: from rats to humans • Rules for LOQ values in " mean percentage of dose " determination • Case 1 : if successive concentrations were found to be below the LOQ, the first one will be replaced by the LOQ value and the other ones will be set below the LOQ. • Case 2: if at least one concentration below the LOQ was included between concentrations above the LOQ, both concentrations will be set to the LOQ value.

  14. Radiation dose calculations: from rats to humans • Calculation of the Effective Dose (D) • Where A is the amount of radioactivity to be administered (usually 1 MBq) • Where Ǻ is the number of transformations in the source region from 1 Bq • of administered drug during the 0 to 336 hours sampling period • Where m is the mass of the source organ (kg)(from ICRP28) • Where Φ is equal to 1 or 0.5 (two differents determinations for GI tract and content) • Where Δ is the mean energy of radiation per nuclear transformation • For 14C= 7.94 x 10-15 kg.Gy/Bq/s

  15. Radiation dose calculations: from rats to humans • Calculation of the Effective Dose (D) (cont ’d) • ICRP 28 mass organ

  16. Radiation dose calculations: from rats to humans • Determination of Å ( for tissues or organs) • whereAUC(0-INF) is equal to: • Cn is the % of dose at the last quantifiable sampling time (LOQ value) • Z is the first order rate constant which is derived from regression analysis of the terminal elimination half-life time (t 1/2 in secondes)

  17. Radiation dose calculations: from rats to humans • Requirements for T1/2 determinations (sec) • Using calculated T1/2 as often as possible is the most conservative approach keeping in mind that is a dosimetric and not a pharmacokinetic approach. • Using T ½ = 100 hours where concentration falls below the LOQ by the final time point and T ½ cannot be determined (excepted for eye where T ½ = 100 days). • T ½ = 100 days (400 days for fat) where concentration does not fall below the LOQ by the final time point and T ½ cannot be determined .

  18. Radiation dose calculations: from rats to humans • Determination of Å ( for GIT and urinary contents)

  19. Radiation dose calculations: from rats to humans • Tissues required for Dosimetry estimation

  20. Radiation dose calculations: from rats to humans • Determination of the CED (Committed Effective Dose) • CED = sum (D x weighing Factor) (a) Red bone marrow = bone marrow x 2 (b) Normally use fat data (adipose or brown fat) (c) Bone surface = bone x 40 (d) MWM corresponds to : Dose relative to content and tissue must be considered for lower large intestine, stomach, oesophagus, bladder and small intestine

  21. Radiation dose calculations: from rats to humans • Rules of replacement for mandatory tissues in CED determination • Conversion factor • Bone, Bone marrow, Breast • Not applicable if the replacement approach has been used • Replacement approach • When? • Organ was not quantified • Not enough concentrations for PK determinations • Why? • In order to increase the CED and decrease the radioactive dose • How? • Using blood data (Blood perfuse organs so dose calculated for blood would be used)

  22. Radiation dose calculations: from rats to humans • How can we anticipate dosimetry issues ?

  23. Radiation dose calculations: from rats to humans • Example 1 • Concentrations determined by QWBRLG • Oral administration at 5 mg/kg • Radioactive dose: 3.7 MBq/Kg or 100 µCi/kg • T 1/2 included in a 35-446 hours range • Faecal elimination equal to 97% (corrected to 100%) • After one week, most of the concentrations was found to be BLQ • No remaining radioactivity levels after 2 weeks • Very large distribution all over the body without specific affinity for tissue • Calculated CED almost based on mandatory tissues

  24. Radiation dose calculations: from rats to humans • CED for example 1 • 2.22 MBq or 60µCi • ( CED = 827 µSv falling within ICRP IIA category)

  25. Radiation dose calculations: from rats to humans • CED for example 1 (cont'd) • List of the additionnal tissues used

  26. Radiation dose calculations: from rats to humans • Example 2 • Concentrations determined by QWBRLG • Intravenous administration at 0.2 mg/kg • Radioactivity dose: 0.74 MBq/Kg or 20 µCi/kg • T 1/2 included in a 123-5000 hours range • After four weeks, only 60% of the total radioactivity was excreted • Urinary elimination equal to 87% (corrected to 100%) • Affinity for tissues • Calculated CED almost based on one mandatory tissue

  27. Radiation dose calculations: from rats to humans • CED for example 2 • 150 KBq or 4 µCi ( to be able to fall within ICRP IIA category)

  28. Radiation dose calculations: from rats to humans • CED for example 2 (cont'd) • List of the additionnal tissues used

  29. Radiation dose calculations: from rats to humans • Example 3 • Concentrations determined by Liquid Scintillation Counting • Oral administration at 20 mg/kg • Radioactive dose: 3.7 MBq/Kg or 100 µCi/kg • T 1/2 included in a 4-100 hours range • Faecal elimination equal to 73% (after 24 hours) (corrected to 100%) • After 24 hours, most of the concentrations was found to be BLQ • No residual radioactivty levels detected after 4 days • Very large distribution all over the body without specific affinity for tissue • Calculated CED almost based on mandatory tissues

  30. Radiation dose calculations: from rats to humans • CED for example 3 • 3.7 MBq or 100 µCi • ( CED = 891 µSv falling within ICRP IIA category)

  31. Radiation dose calculations: from rats to humans • CED for example 3 (cont'd) • List of the additionnal tissues used

  32. Radiation dose calculations: from rats to humans • Conclusions • If a large distribution all over the body was observed with no particular affinity or uptake ( most of % dose  LOQ after 1 or 2 weeks) • If moderate elimination half life times were observed • If faceal elimination is majority to urinary (around a ratio 3/1) • As MRT is a fixed value (not specific for both compounds) • So the CED of GIT content will represent 75% of the final CED

  33. Radiation dose calculations: from rats to humans • Conclusions (cont'd) • If an affinity or uptake in the mandatory tissues was observed • If long elimination half life times were observed • If last quantifiable concentrations were high • So the final CED is closely due to CED of the mandatory tissue(s) • Contribution of GIT and urinary contents will be negligeable

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