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Nuclear imaging to support marketing claims of safety and effectiveness
118
Abstracts
NUCLEAR IMAGING TO SUPPORT MARKETING CLAIMS OF SAFETY AND EFFECTIVENESS Alfred Eric Jones, M.D. There is increased interest in the use of innovative approaches in drug development to enhance knowledge about new drugs and perhaps to lessen the extent of controlled clinical trials. Nuclear imaging can provide such innovation and it promises to play a wider role in drug development. For example, not long ago FDA urged a commercial developer of a quinolone drug to employ PET imaging to attempt to identify patient population characteristics of those who were prone to seizures with this class of anti-infective drugs. Initiating a study using PET both FDA and industry gave credence to the potential use in drug development of a new nuclear imaging method. Within the FDA there is recognition that nuclear imaging methods can be applied to issues encountered in drug development. The problem is learning how to apply a nuclear imaging method without its use having been verified. Commercial drug developers and FDA will require mutual cooperation to understand how to employ nuclear imaging in drug development. Existing and new radiopharmaceuticalswill require more intense scientific development to determine as clearly and completely as possible each radiopharmaceutical'sperformance and characteristics during preclinical studies. Knowledge of these attributes in turn may reveal a preclinical utilization of nuclear imaging that would allow more efficient and intelligent clinical trial design. A new drug's potential promises to be discovered or more precisely defined through nuclear imaging methods. A proposal to use nuclear imaging in the development of a new drug may come from the pharmaceutical industry, academia or from within FDA. In any case, the plan of use should be carefully considered beforehand so that the particular utility of the specific application of nuclear imaging can be optimal. The appropriateness of the imaging data and the eventual method of data analysis also should be agreed upon. The results of the imaging studies should define the effects of a new drug upon physiologic as well as pathophysiologic organ function. Future nuclear imaging methods promise to refine new drug development in a beneficial manner.
THE DEVELOPMENT
OF DRUGS FOR LOW CAPACITY
William C. Eckelman PET Department, Clinical
Center,
National
Institutes
SITES BY NONINVASIVE
of Health,
Bethesda,
IMAGING
MD
Most radiotracers are developed as diagnostic agents with the intent to measure either perfusion or a biochemical reaction by external imaging of the emitted gamma rays. Another interesting use of radiotracers is to determine the relative efficacy of a series of This latter use nonradioactive compounds by displacement of the radioactive probe. expedites the development of new pharmaceuticals in intact animals, and, more importantly, in man by noninvasive means. One such example is the search for a specific Using ‘251 or, in the ideal situation 12% with external imaging, a muscarinic antagonist. series of compounds can be tested for binding to the ml acetylcholine receptor (mAChR) found in the cerebrum and the m2 mAChR found in the heart. One necessary criterion for this study is the high selectivity of the radiotracer for the particular low capacity binding This is most often carried out by using the operational definition of a receptor and site. defining the affinity, the specificity, and correlation with known physiological effect. Once the radiotracer has been validated as a specific probe of the binding site, other nonradioactive compounds can be tested using the radiotracer as a probe. In one paradigm, radiolabeled quinuclidinyl benzilate (QNB) was coinjected with various other halogenated mAChR antagonists and the relative binding in the two target tissues was measured. The ratio of the decreased binding in both tissues indicates the relative selectivity of the In this series, the displacing ability of each compound for each receptor subtypes. nonradioactive compound correlated well with the in vitro affinity constant for the particular target tissue and ml selectivity was observed for the para-iodo and meta-iodo QNB. Another approach is the use of a radiotracer to determine the pharmacokinetics of a This was accomplished by preinjecting the pharmaceutical nonradioactive pharmaceutical. This gives a measure of the unoccupied at various times before injection of the radiotracer. binding sites as a function of time and, therefore, the biological half life. This principle as the radiotracer for angiotensin has been demonstrated using 18F labeled captopril converting enzyme.
Abstracts
NUCLEAR IMAGING TO SUPPORT MARKETING CLAIMS OF SAFETY AND EFFECTIVENESS Alfred Eric Jones, M.D. There is increased interest in the use of innovative approaches in drug development to enhance knowledge about new drugs and perhaps to lessen the extent of controlled clinical trials. Nuclear imaging can provide such innovation and it promises to play a wider role in drug development. For example, not long ago FDA urged a commercial developer of a quinolone drug to employ PET imaging to attempt to identify patient population characteristics of those who were prone to seizures with this class of anti-infective drugs. Initiating a study using PET both FDA and industry gave credence to the potential use in drug development of a new nuclear imaging method. Within the FDA there is recognition that nuclear imaging methods can be applied to issues encountered in drug development. The problem is learning how to apply a nuclear imaging method without its use having been verified. Commercial drug developers and FDA will require mutual cooperation to understand how to employ nuclear imaging in drug development. Existing and new radiopharmaceuticalswill require more intense scientific development to determine as clearly and completely as possible each radiopharmaceutical'sperformance and characteristics during preclinical studies. Knowledge of these attributes in turn may reveal a preclinical utilization of nuclear imaging that would allow more efficient and intelligent clinical trial design. A new drug's potential promises to be discovered or more precisely defined through nuclear imaging methods. A proposal to use nuclear imaging in the development of a new drug may come from the pharmaceutical industry, academia or from within FDA. In any case, the plan of use should be carefully considered beforehand so that the particular utility of the specific application of nuclear imaging can be optimal. The appropriateness of the imaging data and the eventual method of data analysis also should be agreed upon. The results of the imaging studies should define the effects of a new drug upon physiologic as well as pathophysiologic organ function. Future nuclear imaging methods promise to refine new drug development in a beneficial manner.
THE DEVELOPMENT
OF DRUGS FOR LOW CAPACITY
William C. Eckelman PET Department, Clinical
Center,
National
Institutes
SITES BY NONINVASIVE
of Health,
Bethesda,
IMAGING
MD
Most radiotracers are developed as diagnostic agents with the intent to measure either perfusion or a biochemical reaction by external imaging of the emitted gamma rays. Another interesting use of radiotracers is to determine the relative efficacy of a series of This latter use nonradioactive compounds by displacement of the radioactive probe. expedites the development of new pharmaceuticals in intact animals, and, more importantly, in man by noninvasive means. One such example is the search for a specific Using ‘251 or, in the ideal situation 12% with external imaging, a muscarinic antagonist. series of compounds can be tested for binding to the ml acetylcholine receptor (mAChR) found in the cerebrum and the m2 mAChR found in the heart. One necessary criterion for this study is the high selectivity of the radiotracer for the particular low capacity binding This is most often carried out by using the operational definition of a receptor and site. defining the affinity, the specificity, and correlation with known physiological effect. Once the radiotracer has been validated as a specific probe of the binding site, other nonradioactive compounds can be tested using the radiotracer as a probe. In one paradigm, radiolabeled quinuclidinyl benzilate (QNB) was coinjected with various other halogenated mAChR antagonists and the relative binding in the two target tissues was measured. The ratio of the decreased binding in both tissues indicates the relative selectivity of the In this series, the displacing ability of each compound for each receptor subtypes. nonradioactive compound correlated well with the in vitro affinity constant for the particular target tissue and ml selectivity was observed for the para-iodo and meta-iodo QNB. Another approach is the use of a radiotracer to determine the pharmacokinetics of a This was accomplished by preinjecting the pharmaceutical nonradioactive pharmaceutical. This gives a measure of the unoccupied at various times before injection of the radiotracer. binding sites as a function of time and, therefore, the biological half life. This principle as the radiotracer for angiotensin has been demonstrated using 18F labeled captopril converting enzyme.