Safety, pharmacokinetic and dosimetry evaluation of the proposed thrombus imaging agent 99mTc-DI-DD-3B6/22-80B3 Fab'.
OBJECTIVE
(99m)Tc-DI-DD-3B6/22-80B3 (Thromboview, hereafter abbreviated to (99m)Tc-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 (99m)Tc-DI-80B3 Fab' in healthy volunteers.


METHODS
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 (99m)Tc-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.


RESULTS
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. (99m)Tc-DI-80B3 Fab' had a rapid initial plasma clearance (t (1/2)alpha=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.


CONCLUSIONS
(99m)Tc-DI-80B3 Fab' is well tolerated, is rapidly cleared and exhibits clinically acceptable dosimetry-characteristics well suited to a potential thrombus imaging agent.
Macfarlane
David J
DJ
Department of Nuclear Medicine, Royal Brisbane and Women's Hospital, Australia. David_Macfarlane@health.qld.gov.au
Smart
Richard C
RC
Tsui
Wendy W
WW
Gerometta
Michael
M
Eisenberg
Paul R
PR
Scott
Andrew M
AM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D001822:Body Burden; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009928:Organ Specificity; D015609:Organotechnetium Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000175:diagnosis / Q000209:etiology*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012062:Relative Biological Effectiveness; D018570:Risk Assessment; D012307:Risk Factors; D013927:Thrombosis / Q000000981:diagnostic imaging*; D014018:Tissue Distribution; D014915:Whole-Body Counting
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C515867:thromboview