The clinical safety, biodistribution and internal radiation dosimetry of flutemetamol (¹⁸F) injection in healthy Japanese adult volunteers
Michio Senda, David J Brooks, Gill Farrar, Edward J Somer, Carolyn L Paterson, Masahiro Sasaki, Brian J McParland, Michio Senda, David J Brooks, Gill Farrar, Edward J Somer, Carolyn L Paterson, Masahiro Sasaki, Brian J McParland
Abstract
Objectives: The Phase I safety, biodistribution and internal radiation dosimetry study in adult healthy Japanese males of flutemetamol ((18)F) injection, an in vivo β-amyloid imaging agent, is reported and compared with previously obtained Caucasian data.
Methods: Whole-body PET scans of 6 healthy volunteers (age 51.8-61.7 years) were acquired approximately 4 h post-injection (administered activity 102-160 MBq). Venous blood sampling determined (18)F activity concentrations in whole blood and plasma and high-performance liquid chromatography (HPLC) established the percentages of parent [(18)F]flutemetamol and its metabolites. Voided urine activity was recorded. The decay-corrected and normalised (18)F activity of 14 source organ regions as a function of time was entered into the OLINDA/EXM software to calculate the internal radiation dosimetry and effective dose of each subject following the MIRD schema. The pharmacokinetics, biodistribution and dosimetry profiles were compared to data obtained from a cohort of healthy Caucasian adult volunteers from a previous Phase I study of [(18)F]flutemetamol.
Results: Flutemetamol ((18)F) injection was well tolerated. The highest mean initial uptakes were measured in the liver (15.2%), lungs (10.2%) and brain (6.6%). The highest mean radiation absorbed doses were received by the gallbladder wall (366 μGy/MBq), upper large intestine (138 μGy/MBq) and small intestine (121 μGy/MBq). The mean effective dose was 34.9 μSv/MBq. HPLC analysis demonstrated that at 5-min post-injection about 75% of plasma (18)F radioactivity was in the form of parent [(18)F]flutemetamol, reducing to 8 and 2% at 25 and 90 min, respectively, giving rise to less lipophilic (18)F-labelled metabolites. Comparisons with the Caucasian cohort showed no differences that could be regarded as clinically significant.
Conclusion: The clinical safety of [(18)F]flutemetamol demonstrated no differences of clinical significance in the pharmacokinetics, biodistribution and internal radiation dosimetry profiles between Caucasian and Japanese adults.
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References
- Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh compound-B. Ann Neurol. 2004;55:306–319. doi: 10.1002/ana.20009.
- Ikonomovic MD, Klunk WE, Abrahamson EE, Chester AM, Price JC, Tsopelas ND, et al. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzhemeir’s disease. Brain. 2008;131:1630–1645. doi: 10.1093/brain/awn016.
- Leinonen V, Alafuzoff I, Aalto S, Suotunen T, Savolainen S, Någren K, et al. Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with 11C-labeled Pittsburgh compound B. Arch Neurol. 2008;65:1304–1309. doi: 10.1001/archneur.65.10.noc80013.
- Albin RL, Burke JF, Koeppe RA, Giordani B, Gilman S, Frey KA. Assessing mild cognitive impairment with amyloid and dopamine terminal molecular imaging. J Nucl Med. 2013;54:887–893. doi: 10.2967/jnumed.112.112599.
- Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, et al. Imaging β-amyloid burden in aging and dementia. Neurology. 2007;68(20):1718–1725. doi: 10.1212/01.wnl.0000261919.22630.ea.
- Nelissen N, Van Laere K, Thurfjell L, Owenius R, Vandenbulcke M, Koole M, et al. Phase 1 study of the Pittsburg Compound B derivative 18F-flutemetamol in healthy volunteers and patients with probable Alzheimer disease. J Nucl Med. 2009;50:1251–1259. doi: 10.2967/jnumed.109.063305.
- Vandenberghe R, Van Laere K, Ivanoiu A, Salmon E, Bastin C, Triau E, et al. 18F-flutemetamol amyloid imaging in Alzheimer Disease and mild cognitive impairment—a phase 2 trial. Ann Neurol. 2010;68:319–329. doi: 10.1002/ana.22068.
- Wolk DA, Grachev ID, Buckley C, Hala K, Grady MS, Trojanowski JQ, et al. Association between in vivo fluorine-18 labeled Flutemetamol amyloid positron emission tomography imaging and in vivo cerebral cortical histopatholoy. Arch Neurol. 2011;58:1398–1403. doi: 10.1001/archneurol.2011.153.
- Koole M, Lewis DM, Buckley C, Nelissen N, Vandenbulcke M, Vandenberghe D, et al. whole–body biodistribution and radiation dosimetry of 18F-GE067: a radioligand for in vivo brain amyloid imaging. J Nucl Med. 2009;50:818–822. doi: 10.2967/jnumed.108.060756.
- Chen ML. Ethnic or racial differences revisited: impact of dosage regimen and dosage form on pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2006;45(10):957–964. doi: 10.2165/00003088-200645100-00001.
- Johnson JA. Predictability of the effects of race or ethnicity on pharmacokinetics of drugs. Int J Clin Pharmacol. 2000;38(2):53–60. doi: 10.5414/CPP38053.
- McParland BJ. Nuclear medicine radiation dosimetry: advanced theoretical principles. London: Springer-Verlag; 2010.
- ICRP (2003) Basic anatomical and physiological data for use in radiological protection: Reference values. International Commission on Radiological Protection Publication 89, Pergamon Press, Oxford.
- ICRP (1979) Limits for intakes of radionuclides by workers. International Commission on Radiological Protection Publication 30, Pergamon Press, Oxford.
- Cloutier RJ, Smith SA, Watson EE, Snyder WS. Warner GG Dose to the fetus from radionuclides in the bladder. Health Phys. 1973;25:147–161. doi: 10.1097/00004032-197308000-00009.
- ICRP . Radiation dose to patients from radiopharmaceuticals—International Commission on Radiological Protection Publication 80. Oxford: Pergamon Press; 1998.
- Loevinger R, Budinger T, Watson EJ. MIRD primer for absorbed dose calculations. New York: Soc Nucl Med; 1988.
- Stabin MG, Sparks RB, Crow EJ. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 2005;46:1023–1027.
- Cristy M, Eckerman KF (1987) Specific absorbed fractions of energy at various ages from internal photon sources. Volumes I–VII. Oak Ridge (TN): Oak Ridge National Laboratory Report No ORNL/TM-8381.
- ICRP (1991) Recommendations of the International Commission on Radiological Protection. International Commission on Radiological Protection Publication 60, Pergamon Press, Oxford.
Source: PubMed