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New Drug Approvals 2012 - Pt. IX - Florbetapir F 18 (AmyvidTM)

ATC code: V09AX05 (incomplete)

On April 6th, FDA approved Amyvid (Florbetapir F 18), a radiolabeled intravenous imaging agent for the differential diagnosis of Alzheimer's Disease.

Alzheimer's Disease (OMIM 104300, MeSH D000544) is a non-treatable, progressively worsening and fatal disease and the main cause of dementia.
Most commonly affecting the elderly (>65y), it correlates with the growing deposits of aggregating beta amyloid (UniProt P05067) fibrils in the brain, eventually physically destroying it, and abnormal aggregation of the tau protein (UniProt P10636), a microtubule-associated protein inside neurons.
Early symptoms of Alzheimer's include impairment of short term memory, advanced ones, irritability, confusion, aggression, mood swings, and long term memory loss, amongst others.

Diagnosis of Alzheimer's is complicated by overlap of symptoms with other cognitive diseases, and "normal" signs of ageing; sometimes, only brain autopsy (necessarily posthumous) can confirm its presence, while, conversely, patients displaying typical Alzheimer's symptoms sometimes don't show its physiological manifestation. Differential diagnostic techniques include detection of (amongst other biomarkers) amyloid or tau proteins in the spinal fluid, and brain imaging using Positron Emission Tomography (PET), with or without contrast enhancing agents, i.e. radionuclides. A drawback of an early such compound, Pittsburgh compound B (PiB, ChEMBL ID CHEMBL207456, PubChem 2826731), is the short half life (~20 minutes) of the carbon isotope (11C) included. Florbetapir, on the other hand, has a radioactive fluorine isotope (18F) with a half life of ~2 hours, improving its handling and signal strength.

It has to be noted that the presence of plaques, e.g. visualized by PET, and potentially aided by Florbetapir, does not necessarily and sufficiently indicate Alzheimer's; plaques may be present in patients with other neurological disorders, or elderly people with normal cognition. However the absence of significant plaques may rule out the possibility of a patient suffering from Alzheimer's.

Florbetapir (ChEMBL ID CHEMBL1774461, PubChem 24822371) is a radiocompound with molecular weight 360.4 Da, ALogP 3.14, 1 hydrogen bond donor, 4 hydrogen bond acceptors, and thus fully rule of five compliant. It possesses a radioactive isotope of fluorine, 18F, and a C=C double bond in trans / E configuration.
Its systematic (IUPAC) name is 4-[(E)-2-[6-[2-[2-(2-fluoranylethoxy)ethoxy]ethoxy]pyridin-3-yl]ethenyl]-N-methylaniline, Canonical SMILES CNc1ccc(\C=C\c2ccc(OCCOCCOCC[18F])nc2)cc1, Standard InChI=1S/C20H25FN2O3/c1-22-19-7-4-17(5-8-19)2-3-18-6-9-20(23-16-18)26-15-14-25-13-12-24-11-10-21/h2-9,16,22H,10-15H2,1H3/b3-2+/i21-1.

After injection of Amyvid as a single recommended dose of 370 MBq, the agent passes the blood brain barrier and accumulates at amyloid plaques in the patient's brain. 30 to 50 minutes post injection, a 10 minute PET image is acquired.

It is unknown whether Amyvid affects reproductive capacity or causes fetal harm, or whether it is secreted in human milk, but it is not recommended to be used in the respective population. The agent is not indicated for use in pediatric patients. Majority of clinical studies subjects being elderly, no overall differences in safety or effectiveness between them and younger subjects were observed. Because of the agent being radioactive, special precautions have to be taken retrieving, transporting, and administering the agent. The radiation absorbed dose from a single Amyvid dose is 7 mSv in an adult and thus comparable to a chest CT scan, or about twice the normal yearly background dose.
Notable adverse reactions include headache (<2% of patients), musculoskeletal pain, fatigue, nausea (<1%), and anxiety, back pain, increased blood pressure, claustrophobia, feeling cold, insomnia, and neck pain (<0.5%). In early 2011, FDA recommended against approval of Florbetapir, unless structured training programmes for PET readers using Florbetapir would be provided; latest clinical trials of Florbetapir include data from readers either trained manually, or electronically, both proving to be effective.

Amyvid has been developed by Eli Lilly and Company, and Avid Radiopharmaceuticals Inc., its wholly owned subsidiary, and is marketed by Lilly.

The full prescribing information can be found here.


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