Safety, pharmacokinetic and dosimetry evaluation of the proposed thrombus imaging agent 99mTc-DI-DD-3B6/22-80B3 Fab′
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99mTc-DI-DD-3B6/22-80B3 (Thromboview, hereafter abbreviated to 99mTc-DI-80B3 Fab′) is a humanised, radiolabelled monoclonal antibody Fab′ fragment with high affinity and specificity for the D-dimer domain of cross-linked fibrin. The purpose of this study was to evaluate the safety, pharmacokinetics and dosimetry of four increasing doses of 99mTc-DI-80B3 Fab′ in healthy volunteers.
Thirty-two healthy volunteers (18–70 years; 16 male, 16 female) received a single intravenous injection of 0.5, 1.0, 2.0 or 4.0 mg of 99mTc-DI-80B3 Fab′. Safety outcomes (vital signs, electrocardiography, haematology, biochemistry, adverse events and development of human anti-human antibodies) were assessed up to 30 days post injection. Blood and urine samples were collected up to 48 h post injection. Gamma camera images were acquired at 0.5, 1, 2, 4, 6 and 24 h post injection. Dosimetry was performed using standard MIRD methodology.
No adverse events considered to be drug related were observed. Human anti-human antibody was not detectable in any subject during the follow-up period. 99mTc-DI-80B3 Fab′ had a rapid initial plasma clearance (t 1/2α=1 h). The pharmacokinetic profile of the Fab′ fragment was generally linear across the four dose cohorts. By 24 h, 30–35% of the administered radioactivity appeared in the urine. There was marked renal accumulation with time, but no specific uptake was identified within other normal tissues. The effective dose was 9 mSv/750 MBq.
99mTc-DI-80B3 Fab’ is well tolerated, is rapidly cleared and exhibits clinically acceptable dosimetry—characteristics well suited to a potential thrombus imaging agent.
Keywords99mTc Pulmonary embolism Radioimmunodetection
This study was supported by a competitive, peer-reviewed R&D START grant (AusIndustry, Commonwealth Government, Australia) and a research grant from AGEN Biomedical Limited (Acacia Ridge, Queensland, Australia 4110). The authors acknowledge the independent technical editing service provided by ProScribe Medical Communications funded in part by an unrestricted financial grant from AGEN Biomedical Limited. In compliance with the Uniform Requirements for Manuscripts, established by the International Committee of Medical Journal Editors, AGEN did not impose any impediment, directly or indirectly, on the publication of the study’s results. Dr. Macfarlane was the principal investigator during the study. Dr. Macfarlane currently acts as a consultant to AGEN Biomedical Limited for product and protocol development. Professor Eisenberg is also a consultant to AGEN Biomedical Limited and Dr. Gerometta is an employee of AGEN Biomedical Limited. Wendy Tsui is employed by the University of New South Wales under a research contract between AGEN Biomedical Limited and the University. We would like to acknowledge Q-Pharm staff for assisting with the conduct of the study.
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