A stylized computational model of the rat for organ dosimetry in support of preclinical evaluations of peptide receptor radionuclide therapy with (90)Y, (111)In, or (177)Lu.
The therapeutic effects of peptide receptor-based radionuclide therapy are extensively being investigated in rats bearing tumors. Both the dose to the tumor and the therapy-limiting dose to normal tissues, such as kidneys and bone marrow, are of interest for these preclinical studies. The aim of this work was to develop a generalized computational model for internal dosimetry in rats.


METHODS
Mature rats were dissected and the relative positions, dimensions, and weights of all of their major organs were measured. A mathematic model was set up for the rat body and its internal organs to enable Monte Carlo radiation transport calculations to determine estimates for both tumor and organ self-doses as cross-organ doses for (90)Y, (111)In, and (177)Lu. The organs and body were mostly of ellipsoid shape with the axes given as the measured length, width, and height normalized to values that, together with the measured weights, are consistent with the recommended soft-tissue and bone densities. A spheric tumor of 0.25 g was positioned on the right femur. Calculations were performed with the Monte Carlo neutral particle transport code MCNP for the beta-emitters (maximum energy, 2.28 MeV) and (177)Lu (maximum energy, 0.497 MeV) and for the gamma-emissions from (177)Lu and from (111)In. The presented absorbed dose S values are used to calculate the absorbed dose estimates for the rat organs in a study on the biodistribution of (177)Lu-DOTA-Tyr(3)-octreotate (DOTA is 1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid). Three activity distributions were considered in the kidney: uniform in the whole kidney, in the cortex, or in the outer 1-mm-thick rim of the cortex. Isodose curves and dose volume histograms were calculated for the dose distribution to the kidneys.


RESULTS
Depending on the activity distribution in the kidneys, the renal dose for (177)Lu-DOTA-Tyr(3)-octreotate is 0.13-0.17 mGy/MBq.


CONCLUSIONS
The renal dose of 70-95 Gy for an injected activity of 555 MBq will likely cause radiation damage, although the higher amount of peptide with this activity may influence the dosimetry by partial receptor saturation. Dose volume histograms show that (111)In and (177)Lu are likely to have a higher threshold for renal damage than (90)Y.
Konijnenberg
Mark W
MW
Mallinckrodt Medical, Tyco Healthcare, Petten, The Netherlands. mark.konijnenberg@emea.tycohealthcare.com
Bijster
Magda
M
Krenning
Eric P
EP
De Jong
Marion
M
D000818:Animals; D001822:Body Burden; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005266:Femoral Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D007205:Indium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D008187:Lutetium / Q000493:pharmacokinetics / Q000627:therapeutic use; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D015282:Octreotide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D009928:Organ Specificity; D011829:Radiation Dosage; D011868:Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011874:Radiometry / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D051381:Rats; D017208:Rats, Wistar; D012062:Relative Biological Effectiveness; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use
D007205:Indium Radioisotopes; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; D008187:Lutetium; D015282:Octreotide; C106246:Edotreotide