Radiopharmaceutical supply and demand in the era of precision medicine
June 16, 2017
By Michael L. Nickels, Michael L. Schulte and H. Charles Manning
In recent years, medical imaging, including magnetic resonance imaging (MRI), X-ray, computed tomography (CT), ultrasound, optical and positron emission tomography (PET), has reached the forefront of indispensable tools used by medical doctors to diagnose, treat and monitor the cellular and molecular underpinnings of diseases on a patient-by-patient basis.
With the increasing need for more information to be gained from each individual diagnostic test, scientists have been harnessing the characteristics of diseases unique to each patient to aid in determination of treatment planning. Surveys of the distinctive chemistries of individual tissues within a living organism cannot be accomplished with classic anatomical imaging techniques, such as X-ray, CT and ultrasound, but require molecular imaging techniques, such as PET. No other individual test can be claimed to be more influential for the growth of PET above 2-deoxy-2(18F)fluoro-D-glucose or [18F]FDG.
Early studies found that synthetic analogs of glucose containing a fluorine in place of a hydroxyl group in the 2 position of the carbohydrate backbone were easily and rapidly taken up by cells, but became trapped within the cells as the normal glucose metabolic pathways could not progress past the first phosphorylation event.
This resulted in an accumulation of these glucose analogs within the cell and could, by extension, be seen within cells with elevated glycolytic activity, such as rapidly proliferating cancer cells. By replacing the normal fluorine atom in these compounds with the radioactive isotope fluorine-18, [18F]FDG PET was born. First administered to healthy human volunteers in 1976, the compound quickly gained favor as an imaging agent for a variety of neuropsychiatric disorders, but arguably found its greatest utilization in the world of oncology.
With the rapidly evolving technology of both producing [18F]FDG and detecting the radioactivity produced in a three dimensional field of view, the supply of the drug has far out-weighed the demand in recent years. One could argue that the technology involved in the production of [18F]FDG, primarily the cyclotron production of the raw fluorine-18 and the automated synthetic units used to produce the drug, has outpaced the demand for the drug in such a way that the field has been flush with availability, causing a dramatic downturn in the price per dose in recent years. In reality, the relatively low cost per dose of [18F]FDG has been a benefit for facilities that purchase the drug from commercial vendors, but has been highly detrimental to the facilities that prepare the drug for internal use and rely on reimbursement to subsidize the cost of production and auxiliary research and development.
The utility of [18F]FDG, although shown to be useful in a variety of circumstances, is limited for visualization of the brain due to high background uptake in normal brain tissue. For example, the determination of amyloid plaques associated with neurodegenerative disease requires the development of alternative imaging agents. In recent years, several new PET imaging agents have been brought to market through commercial entities and academics alike.
The first major effort was undertaken by Avid Radiopharmaceuticals for the commercialization of [18F]Florbetapir (known as AMYVID or AV-45). With FDA approval being granted in early 2011, [18F]Florbetapir showed great promise of becoming a sustainable new PET imaging agent. However, the proper utilization of the drug hinged on a therapeutic agent also coming to market, which to date, has not been the case.
Even though the future of [18F]Florbetapir remains uncertain, release of new amyloid imaging agents has not been hampered. The most recent approval for a novel PET imaging agent has been [18F]Fluciclovine (known as 18F-FACBC), gaining FDA approval in May of 2016. This agent has gained interest in the oncology community, especially in prostate cancer, and is currently gearing up for large-scale production and distribution through a partnership with Blue Earth Diagnostics (the developer of [18F]Fluciclovine) and Siemens’ PETNET Solutions. Lastly, one cannot ignore the success of [18F]Florbetaben (formerly known as BAY-949172), which was originally developed by Bayer and gained FDA acceptance in 2015.
With all three of these agents competing for the top spot as the next highly used PET imaging agent, the future of this field does indeed look promising. Additionally, a large number of new PET agents are being reported and tested each day in both pharmaceutical companies and academia, utilizing other PET isotopes, including carbon-11, gallium-68 and zirconium-89. With the advent of new radiopharmaceuticals and increasing utilization in the pursuit of precision medicine, future applications of PET are nearly unlimited.
About the authors: Michael L. Nickels, Ph.D., is the technical director of the PET Radiochemistry Research Laboratories, Radiology and Radiological Sciences at Vanderbilt University. Michael Schulte, Ph.D., is a research instructor at Vanderbilt University. H. Charles Manning, Ph.D., is the director, Vanderbilt Center for Molecular Probes and Molecular Imaging Research.
In recent years, medical imaging, including magnetic resonance imaging (MRI), X-ray, computed tomography (CT), ultrasound, optical and positron emission tomography (PET), has reached the forefront of indispensable tools used by medical doctors to diagnose, treat and monitor the cellular and molecular underpinnings of diseases on a patient-by-patient basis.
With the increasing need for more information to be gained from each individual diagnostic test, scientists have been harnessing the characteristics of diseases unique to each patient to aid in determination of treatment planning. Surveys of the distinctive chemistries of individual tissues within a living organism cannot be accomplished with classic anatomical imaging techniques, such as X-ray, CT and ultrasound, but require molecular imaging techniques, such as PET. No other individual test can be claimed to be more influential for the growth of PET above 2-deoxy-2(18F)fluoro-D-glucose or [18F]FDG.
Early studies found that synthetic analogs of glucose containing a fluorine in place of a hydroxyl group in the 2 position of the carbohydrate backbone were easily and rapidly taken up by cells, but became trapped within the cells as the normal glucose metabolic pathways could not progress past the first phosphorylation event.
This resulted in an accumulation of these glucose analogs within the cell and could, by extension, be seen within cells with elevated glycolytic activity, such as rapidly proliferating cancer cells. By replacing the normal fluorine atom in these compounds with the radioactive isotope fluorine-18, [18F]FDG PET was born. First administered to healthy human volunteers in 1976, the compound quickly gained favor as an imaging agent for a variety of neuropsychiatric disorders, but arguably found its greatest utilization in the world of oncology.
With the rapidly evolving technology of both producing [18F]FDG and detecting the radioactivity produced in a three dimensional field of view, the supply of the drug has far out-weighed the demand in recent years. One could argue that the technology involved in the production of [18F]FDG, primarily the cyclotron production of the raw fluorine-18 and the automated synthetic units used to produce the drug, has outpaced the demand for the drug in such a way that the field has been flush with availability, causing a dramatic downturn in the price per dose in recent years. In reality, the relatively low cost per dose of [18F]FDG has been a benefit for facilities that purchase the drug from commercial vendors, but has been highly detrimental to the facilities that prepare the drug for internal use and rely on reimbursement to subsidize the cost of production and auxiliary research and development.
The utility of [18F]FDG, although shown to be useful in a variety of circumstances, is limited for visualization of the brain due to high background uptake in normal brain tissue. For example, the determination of amyloid plaques associated with neurodegenerative disease requires the development of alternative imaging agents. In recent years, several new PET imaging agents have been brought to market through commercial entities and academics alike.
The first major effort was undertaken by Avid Radiopharmaceuticals for the commercialization of [18F]Florbetapir (known as AMYVID or AV-45). With FDA approval being granted in early 2011, [18F]Florbetapir showed great promise of becoming a sustainable new PET imaging agent. However, the proper utilization of the drug hinged on a therapeutic agent also coming to market, which to date, has not been the case.
Even though the future of [18F]Florbetapir remains uncertain, release of new amyloid imaging agents has not been hampered. The most recent approval for a novel PET imaging agent has been [18F]Fluciclovine (known as 18F-FACBC), gaining FDA approval in May of 2016. This agent has gained interest in the oncology community, especially in prostate cancer, and is currently gearing up for large-scale production and distribution through a partnership with Blue Earth Diagnostics (the developer of [18F]Fluciclovine) and Siemens’ PETNET Solutions. Lastly, one cannot ignore the success of [18F]Florbetaben (formerly known as BAY-949172), which was originally developed by Bayer and gained FDA acceptance in 2015.
With all three of these agents competing for the top spot as the next highly used PET imaging agent, the future of this field does indeed look promising. Additionally, a large number of new PET agents are being reported and tested each day in both pharmaceutical companies and academia, utilizing other PET isotopes, including carbon-11, gallium-68 and zirconium-89. With the advent of new radiopharmaceuticals and increasing utilization in the pursuit of precision medicine, future applications of PET are nearly unlimited.
About the authors: Michael L. Nickels, Ph.D., is the technical director of the PET Radiochemistry Research Laboratories, Radiology and Radiological Sciences at Vanderbilt University. Michael Schulte, Ph.D., is a research instructor at Vanderbilt University. H. Charles Manning, Ph.D., is the director, Vanderbilt Center for Molecular Probes and Molecular Imaging Research.