A multi-species, multi-site study of the radiation dosimetry of [11C] erlotinib, a radiolabeled tyrosine kinase inhibitor

1024 Objectives Erlotinib is a tyrosine kinase inhibitor (TKI) clinically prescribed for non-small cell lung cancer (NSCLC) patients bearing epidermal growth factor receptor (EGFR) point mutations in the kinase domain. By radiolabeling erlotinib, researchers can assess whole body EGFR sensitivity to TKIs. Our objectives were to (1) establish a human dosimetric profile of [11C] erlotinib and (2) assess the consistency of calculated radiation exposure across species using the same human model. This study afforded a unique opportunity to assess how well dosimetry analyses agreed between 4 different species. Methods Subjects examined in this multi-site study included: 3 healthy (1 female, 2 male) rhesus macaque monkeys (Yale), 1 healthy male landrace pig (Aarhus), 4 male, WT EGFR tumor-bearing, athymic nude-Fox1nu mice (Hadassah), and a female, stage 3a NSCLC patient (VU) with exon 19 deletion mutation present in EGFR kinase domain. After low-dose CT scanning, subjects were given a bolus injection of [11C] erlotinib. Mean injected activity was 175 ± 12.5 MBq for monkeys, 299 MBq for the pig, 17.9 ± 3.5 MBq for mice, and 403 MBq for the human subject. PET data of the whole body were acquired dynamically for up to 120 min. Regions of interest (ROIs) were manually drawn (when identifiable) from CT scans in order to extract time activity curves (TACs) from the following organs: gall bladder, heart, kidneys, liver, lungs, and urinary bladder. TACs were used to calculate residence time in each organ (eqn. 1). Residence times were used to calculate the absorbed radiation dose (per unit injected [11C] erlotinib) via OLINDA [1]. All animal data were used to predict organ exposures in a 70 kg human male. Eqn. 1. RT = [int(TAC)/ID][asterisk]V[asterisk]S RT = residence time TAC = dynamic time activity curve of organ ID = injected dose V = model organ volume S = species specific scale factor Results n monkeys, mice, and human, the liver was identified as the organ of greatest radiation exposure (critical organ) with respective mean exposures of 1.95E-2 ± 2.86E-3 mSv/MBq, 1.54E-2 ± 2.28E-3 mSv/MBq, and 5.01E-2 mSv/MBq. Mouse and monkey radiation exposures in the liver were not statistically different (p=0.12). The critical organ based on the pig data was the gall bladder wall (2.03E-2 mSv/MBq) but the liver had a very similar radiation exposure (1.96E-2 mSv/MBq). Across species, brain and bone exposure was minimal. A complete list of organ exposures can be found in figure 1. References: [1] Stabin MG et al. J Nucl Med 2005; 46, 1023-1027. [2] Petrulli JR et al. Neoplasia 2013; 15, 1347-1353. Conclusions (1) When designing PET studies using [11C] erlotinib, the liver should be considered the critical organ. Digestive organs such as the gallbladder, intestines, and kidneys also experience relatively high radiation exposure. (2) Despite minor discrepancies, the dosimetric profile of [11C] erlotinib was quite consistent whether it was derived from human, monkey, pig, or mouse data. Because erlotinib only specifically binds kinase domain mutant EGFR [2], it should be noted that only non-specific binding was present in all subjects except for the human (whose cancer expressed kinase domain mutant EGFR). Research Support: R01 CA195493-01. Yale PET Center. JRP is supported by the NSF GRFP (DGE-1122492). References: [1] Stabin MG et al. J Nucl Med 2005; 46, 1023-1027. [2] Petrulli JR et al. Neoplasia 2013; 15, 1347-1353.