"The U.S. Food and Drug Administration today approved Vizamyl (flutemetamol F 18 injection), a radioactive diagnostic drug for use with positron emission tomography (PET) imaging of the brain in adults being evaluated for Alzheimer's disease (AD) "...
Mechanism Of Action
Florbetaben F18 is a F18-labeled stilbene derivative, which binds to β-amyloid plaques in the brain. The F 18 isotope produces a positron signal that is detected by a PET scanner. 3H-florbetaben in vitro binding experiments reveal two binding sites (Kd of 16 nM and 135 nM) in frontal cortex homogenates from patients with AD. Binding of florbetaben F18 to β-amyloid plaques in post-mortem brain sections from patients with AD using autoradiography correlates with both immunohistochemical and Bielschowsky silver stains. Florbetaben F 18 does not bind to tau or α-synuclein in tissue from patients with AD. Neither Neuraceq nor non-radioactive florbetaben F 19 bind to AT8 positive tau deposits in brain tissue from patients with frontotemporal dementia (FTD), using autoradiography and immunohistochemistry, respectively.
Following intravenous administration, Neuraceq crosses the blood brain barrier and shows differential retention in brain regions that contain β-amyloid deposits. Differences in signal intensity between brain regions showing specific and nonspecific Neuraceq uptake form the basis for the image interpretation method.
Ten minutes after intravenous bolus injection of 300 MBq of Neuraceq in human volunteers, approximately 6% of the injected radioactivity was distributed to the brain. Florbetaben F 18 plasma concentrations declined by approximately 75% at 20 minutes post-injection, and by approximately 90% at 50 minutes. The F 18 in circulation during the 45130 minute imaging window was principally associated with polar metabolites of florbetaben. Florbetaben F 18 was 98.5% bound to plasma proteins and was eliminated from plasma primarily via the hepatobiliary route with a mean biological half-life of approximately 1 hour. In vitro studies show that metabolism of florbetaben is predominantly catalyzed by CYP2J2 and CYP4F2. At 12 hours post-administration, approximately 30% of the injected radioactivity had been excreted in urine. Almost all F18 radioactivity in urine was excreted as polar metabolites of florbetaben F18 and only trace amounts of florbetaben F18 were detected.
In in vitro studies using human liver microsomes, florbetaben did not inhibit cytochrome P450 enzymes at concentrations present in vivo.
Neuraceq was evaluated in three single arm clinical studies (Study A-C) that examined images from adults with a range of cognitive function, including some end-of-life patients who had agreed to participate in a post-mortem brain donation program. Subjects underwent Neuraceq injection and scan, then had images interpreted by independent readers masked to all clinical information.
The Standard of Truth (SoT) was based on the histopathologic examination using Bielschowsky silver staining (BSS) of six brain regions assessed by a Pathology Consensus Panel masked to all clinical information (including PET scan results). Neuraceq PET imaging results (negative or positive) corresponded to a histopathology derived plaque score based on the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria using neuritic plaque counts (Table 5). For the subject level SoT, if in any of the six regions β-amyloid neuritic plaques were more than sparse, the subject was classified as positive; if in none of the regions the β-amyloid neuritic plaques were assessed as being more than sparse, the subject was classified as negative.
Table 5: β-Amyloid Neuritic Plaque Counts Correlation
to Image Results
|Plaque Counts||CERAD Score||Neuraceq PET Image Result|
|1 – 5||Sparse|
|6 – 19||Moderate||Positive|
Study A evaluated Neuraceq PET images from 205 subjects and compared the results to postmortem truth standard assessments of brain β-amyloid neuritic plaque density in subjects who died during the study. The median age was 79 years (range 48 to 98 years) and 52% of the subjects were male. By medical history 137 study participants had AD, 31 had other non-AD dementia, 5 had dementia with Lewy Bodies (DLB), and 32 had no clinical evidence of dementia. Interpretation of images from 82 autopsied subjects was compared to the subject level histopathology SoT. Three readers, after undergoing in-person tutoring, interpreted images using a clinically applicable image interpretation methodology [see DOSAGE AND ADMINISTRATION]. At autopsy, the subject level brain β-amyloid neuritic plaque density category was: frequent (n = 31); moderate (n = 21); sparse (n = 17); or none (n = 13). Results from Study A are presented in Table 6 and Table 7.
In Study B five independent, blinded readers underwent the Electronic Media Training in the clinically applicable image interpretation methodology [see DOSAGE AND ADMINISTRATION] and assessed images from the same 82 end-of-life subjects who enrolled in Study A. The time interval between the Neuraceq scan and death was less than one year for 45 patients, between one and two years for 23 patients and more than two years for 14 patients. Results from Study B can also be found in Table 6 and Table 7.
Study C evaluated the reliability and reproducibility of the clinically applicable image interpretation methodology [see DOSAGE AND ADMINISTRATION] using the Electronic Media Training; 461 images from previous clinical studies were included from subjects with a range of diagnoses. Five new readers assessed randomly provided images from subjects with a truth standard (54 subjects who underwent an autopsy) and without a truth standard (51 subjects with mild cognitive impairment, 182 subjects with AD, 35 subjects with other dementias, 5 subjects with Parkinson's Disease and 188 healthy volunteers). Among the 461 subjects, the median age was 72 years (range 22 to 98), 197 were females, and 359 were Caucasian. Image reproducibility data for various subject groups in Study C are presented in Table 8. Inter-reader agreement across all 5 readers had a kappa coefficient of 0.79 (95% CI 0.77, 0.83). The performance characteristics in 54 subjects with SoT were similar to those measured in Studies A and B. Additionally, intra-reader reproducibility was assessed from 46 images (10%); the percentage of intra-reader agreement for the 5 readers ranged from 91% to 98%.
Table 6: Neuraceq Results by Reader Training Method
using BSS as Standard of Truth
|Read Result||In-Person Training (Study A)
|Electronic Media Training (Study B)
|Range among the readers||96-98||90 -100|
|Range among the readers||77-83||47-80|
Table 7: Neuraceq Correct
and Erroneous Read Results by Reader Training Method
|Read Result||In-Person Training (Study A)||Electronic Media Training (Study B)|
|BSS was the Histopathology Standard of Truth|
Table 8: Reproducibility of
Scan Results among Readers in Various Subject Groupsa
|Subject Group by Cognitive Status and Standard of Truth (SoT)||Positive Scans nb||Kappa (95% CI)||Percent of Scans with Inter-reader Agreement|
|3 of 5 readers agreed||4 of 5 readers agreed||5 of 5 readers agreed|
|All subjects (n=454)||212||0.80 (0.77, 0.83)||6||15||78|
|Subjects without SoT (n=394)||175||0.80 (0.77, 0.83)||6||15||79|
|Subjects with SoT (n=60)||37||0.75 (0.67, 0.83)||10||15||75|
|AD (n=176)||139||0.77 (0.72, 0.81)||7||10||83|
|HV (n=188)||26||0.55 (0.49, 0.58)||7||15||77|
|MCI (n=50, all without SoT)||28||0.84 (0.75, 0.92)||0||20||80|
|Other Dementias (n=40)||18||0.65 (0.55, 0.74)||8||33||60|
|aSubjects with missing scan interpretation (2 to 6% per
group) were excluded from the analyses.
bShown is the median number of scans interpreted as positive across the 5 readers for each group of subjects listed in the first column.
Alzheimer's disease (AD), Mild cognitive impairment (MCI), healthy volunteer (HV). Other dementias include DLB, fronto-temporal lobe dementia, vascular dementia, and dementia associated with PD.
Last reviewed on RxList: 3/31/2014
This monograph has been modified to include the generic and brand name in many instances.
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