Michel Koole1, Talakad G Lohith2, John L Valentine3, Idriss Bennacef4, Ruben Declercq5, Tom Reynders5, Kerry Riffel4, Sofie Celen6, Kim Serdons1, Guy Bormans6, Sandrine Ferry-Martin7, Philippe Laroque7, Abbas Walji8, Eric D Hostetler4, Richard J Briscoe3, Jan de Hoon9, Cyrille Sur4, Koen Van Laere1, Arie Struyk10. 1. Division of Nuclear Medicine, Leuven University Hospitals and UZ Leuven, Leuven, Belgium. 2. Translational Imaging Biomarkers, Merck & Co., Inc., 770 Sumneytown Pike, Mailstop WP44D-216, West Point, PA, 19486, USA. talakad.lohith@merck.com. 3. Safety Assessment and Laboratory Animal Research, Merck & Co., Inc., West Point, PA, USA. 4. Translational Imaging Biomarkers, Merck & Co., Inc., 770 Sumneytown Pike, Mailstop WP44D-216, West Point, PA, 19486, USA. 5. Translational Pharmacology Europe, Merck Sharp & Dohme Inc., Brussels, Belgium. 6. Radiopharmaceutical Research, KU Leuven, Leuven, Belgium. 7. Safety Assessment and Laboratory Animal Research, Merck Sharp & Dohme, Riom, France. 8. Discovery Chemistry, Merck & Co., Inc., West Point, PA, USA. 9. Center for Clinical Pharmacology, University Hospitals of Leuven, Leuven, Belgium. 10. Translational Pharmacology, Merck & Co., Inc., North Wales, PA, USA.
Abstract
PURPOSE: [18F]MK-6240 is a selective, high-affinity positron emission tomography tracer for imaging neurofibrillary tangles, a key pathological signature that correlates with cognitive decline in Alzheimer disease. This report provides safety information from preclinical toxicology studies and first-in-human whole-body biodistribution and dosimetry studies of [18F]MK-6240 for its potential application in human brain imaging studies. PROCEDURES: MK-6240 was administered intravenously (IV) in a 7-day rat toxicity study at × 50, × 100, and × 1000 dose margins relative to projected highest clinical dose of 0.333 μg/kg. The IV formulation of MK-6240 for clinical use and the formulation used in the 7-day rat toxicity study was tested for hemolysis potential in human and Wistar rat whole blood. Sequential whole-body positron emission tomography scans were performed in three healthy young subjects after IV bolus injection of 180 ± 0.3 MBq [18F]MK-6240 to characterize organ biodistribution and estimate whole-body radiation exposure (effective dose). RESULTS: MK-6240 administered IV in a 7-day rat toxicity study did not show any test article-related changes. The no-observed-adverse-effect level in rats was ≥ 333 μg/kg/day which provides a margin 1000-fold over an anticipated maximum clinical dose of 0.333 μg/kg. Additionally, the MK-6240 formulation was not hemolytic in human or Wistar rat blood. [18F]MK-6240 activity was widely distributed to the brain and the rest of the body, with organ absorbed doses largest for the gall bladder (202 μGy/MBq). The average (±SD) effective dose was 29.4 ± 0.6 μSv/MBq, which is in the typical range for F-18 radiolabeled ligands. CONCLUSIONS: Microdoses of [18F]MK-6240 are safe for clinical positron emission tomography imaging studies. Single IV administration of 185 MBq (5 mCi) [18F]MK-6240 is anticipated to result in a total human effective dose of 5.4 mSv and thus allows multiple positron emission tomography scans of the same subject per year.
PURPOSE: [18F]MK-6240 is a selective, high-affinity positron emission tomography tracer for imaging neurofibrillary tangles, a key pathological signature that correlates with cognitive decline in Alzheimer disease. This report provides safety information from preclinical toxicology studies and first-in-human whole-body biodistribution and dosimetry studies of [18F]MK-6240 for its potential application in human brain imaging studies. PROCEDURES: MK-6240 was administered intravenously (IV) in a 7-day rattoxicity study at × 50, × 100, and × 1000 dose margins relative to projected highest clinical dose of 0.333 μg/kg. The IV formulation of MK-6240 for clinical use and the formulation used in the 7-day rattoxicity study was tested for hemolysis potential in human and Wistar rat whole blood. Sequential whole-body positron emission tomography scans were performed in three healthy young subjects after IV bolus injection of 180 ± 0.3 MBq [18F]MK-6240 to characterize organ biodistribution and estimate whole-body radiation exposure (effective dose). RESULTS:MK-6240 administered IV in a 7-day rattoxicity study did not show any test article-related changes. The no-observed-adverse-effect level in rats was ≥ 333 μg/kg/day which provides a margin 1000-fold over an anticipated maximum clinical dose of 0.333 μg/kg. Additionally, the MK-6240 formulation was not hemolytic in human or Wistar rat blood. [18F]MK-6240 activity was widely distributed to the brain and the rest of the body, with organ absorbed doses largest for the gall bladder (202 μGy/MBq). The average (±SD) effective dose was 29.4 ± 0.6 μSv/MBq, which is in the typical range for F-18 radiolabeled ligands. CONCLUSIONS: Microdoses of [18F]MK-6240 are safe for clinical positron emission tomography imaging studies. Single IV administration of 185 MBq (5 mCi) [18F]MK-6240 is anticipated to result in a total human effective dose of 5.4 mSv and thus allows multiple positron emission tomography scans of the same subject per year.
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