title: Renal uptake of bismuth-213 and its contribution to kidney radiation dose following administration of actinium-225-labeled antibody.
abstract: Clinical therapeutic studies using (225)Ac-labeled antibodies have begun. Of major concern is renal toxicity that may result from the three alpha-emitting progeny generated following the decay of (225)Ac. The purpose of this study was to determine the amount of (225)Ac and non-equilibrium progeny in the mouse kidney after the injection of (225)Ac-huM195 antibody and examine the dosimetric consequences. Groups of mice were sacrificed at 24, 96 and 144 h after injection with (225)Ac-huM195 antibody and kidneys excised. One kidney was used for gamma ray spectroscopic measurements by a high-purity germanium (HPGe) detector. The second kidney was used to generate frozen tissue sections which were examined by digital autoradiography (DAR). Two measurements were performed on each kidney specimen: (1) immediately post-resection and (2) after sufficient time for any non-equilibrium excess (213)Bi to decay completely. Comparison of these measurements enabled estimation of the amount of excess (213)Bi reaching the kidney (γ-ray spectroscopy) and its sub-regional distribution (DAR). The average absorbed dose to whole kidney, determined by spectroscopy, was 0.77 (SD 0.21) Gy kBq(-1), of which 0.46 (SD 0.16) Gy kBq(-1) (i.e. 60%) was due to non-equilibrium excess (213)Bi. The relative contributions to renal cortex and medulla were determined by DAR. The estimated dose to the cortex from non-equilibrium excess (213)Bi (0.31 (SD 0.11) Gy kBq(-1)) represented ∼46% of the total. For the medulla the dose contribution from excess (213)Bi (0.81 (SD 0.28) Gy kBq(-1)) was ∼80% of the total. Based on these estimates, for human patients we project a kidney-absorbed dose of 0.28 Gy MBq(-1) following administration of (225)Ac-huM195 with non-equilibrium excess (213)Bi responsible for approximately 60% of the total. Methods to reduce renal accumulation of radioactive progeny appear to be necessary for the success of (225)Ac radioimmunotherapy.
authors.affiliation: Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. schwarj1@mskcc.org
authors.forename: J
authors.initials: J
authors.lastname: Schwartz
authors.forename: J S
authors.initials: JS
authors.lastname: Jaggi
authors.forename: J A
authors.initials: JA
authors.lastname: O'Donoghue
authors.forename: S
authors.initials: S
authors.lastname: Ruan
authors.forename: M
authors.initials: M
authors.lastname: McDevitt
authors.forename: S M
authors.initials: SM
authors.lastname: Larson
authors.forename: D A
authors.initials: DA
authors.lastname: Scheinberg
authors.forename: J L
authors.initials: JL
authors.lastname: Humm
mesh_terms: D000186:Actinium / Q000009:adverse effects / Q000737:chemistry*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000737:chemistry*; D001345:Autoradiography; D001692:Biological Transport; D001729:Bismuth / Q000378:metabolism*; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D011829:Radiation Dosage; D011868:Radioisotopes / Q000378:metabolism*; D011874:Radiometry
chemical_list: D000906:Antibodies; D011868:Radioisotopes; D000186:Actinium; D001729:Bismuth