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.

Figures

Fig. 1
Fig. 1
Collapsed coronal images of a representative subject following administration of flutemetamol (18F) injection acquired at times of (left to right) 0.10, 0.55, 1.20, 2.57 and 3.94 h post-injection
Fig. 2
Fig. 2
Mean decay-corrected 18F activity values in brain, liver, urine and intestinal contents for all six subjects as functions of time following administration of flutemetamol (18F) Injection. Error bars are drawn at ±1 standard deviation and urine and intestinal contents curves have been offset slightly for clarity
Fig. 3
Fig. 3
Decay-corrected 18F activity concentration in whole blood and plasma for all six subjects as a function of time following administration of flutemetamol (18F) injection. Data points, offset for clarity, are mean values and uncertainty error bars are ±1 standard deviation. Plasma data from a previous Caucasian study (ALZ103) [6] are also shown for comparison
Fig. 4
Fig. 4
HPLC radiochromatograms for a plasma sample spiked ex vivo with standard [18F]flutemetamol, and for the plasma obtained from a representative subject at b 5, c 30 and d 90 min after administration of flutemetamol (18F) injection. The vertical axis shows “Radioactivity detector response (mV)” while the “Retention time (min)” appears on the horizontal axis. Region 3 corresponds to the [18F]flutemetamol parent in b, c and d as identified in a. Regions 1 and 2 correspond to metabolites that are more hydrophilic than the parent of Region 3, and Region 4 represents a minor lipophilic metabolite
Fig. 5
Fig. 5
Mean areas-under-the-curve for radiochromatograms for [18F]flutemetamol parent and 18F-labelled metabolities in plasma as function of time following administration of flutemetamol (18F) injection. Error bars are ±1 standard deviation. The fraction of the parent compound ([18F]flutemetamol) in the plasma decreased from 75 % at 5 min to 8.3 % at 25 min with the majority of the plasma activity bound to hydrophilic metabolites

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