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Imaging Technology and Clinical Target Site PK and PD Assessments: Emerging Opportunities and Potential Limitations
Tuesday, November 13
7:00 am – 8:15 am
Sunrise Session
ACPE #073-999-07-540-L04
Imaging technology is currently fueling a revolution in target site measurements that may change drug development methodologies by accelerating development and regulatory approval timelines. Topics such as biophase pharmacokinetics (PK), site-specific PK, and real-time inhibition/activation assessments will be covered.
Clinical PK generally relies on drug concentration measurements from the two most easily accessible matrices; blood and urine. Unfortunately, most drugs do not distribute uniformly in the body, thus PK measurements can be poor predictors of the active site concentrations of the therapeutic agent. Historically, clinical researchers have been limited by a lack of appropriate non-invasive methodology for direct target site assessment of in vivo tissue drug distribution. Today, this paradigm is changing. There are at least three therapeutic areas of drug development, namely antimicrobials, antineoplastics, and CNS agents, where studies reporting results from precise and noninvasive target site PK measurements are becoming almost routine. In particular for CNS drugs, Positron Emission Tomography (PET) technology is routinely utilized to generate time-activity curves, which are then fitted by compartmental modeling to estimate receptor occupancies, binding affinities, and binding potential of CNS drugs directly at their site of action. In addition to noninvasive in vivo imaging of drug PK at the site of action, imaging technology has also great potential to demonstrate efficacy in many target diseases, at the organ, tissue and even cellular level. This potential of imaging as biomarker of PD response is addressed in a series of nine Critical Path Opportunities. Furthermore, the FDA has singled out imaging as a “key technology for assessing, accelerating development and guiding use of new therapeutic options”. The recently introduced Exploratory IND Studies Guidance specifically addresses performing single dose PK and imaging studies to gain early information on the drug’s biodistribution and target interaction characteristics. For drugs that can be directly radiolabeled, noninvasive functional imaging can be of tremendous value in directly determining drug distribution and time course of binding, establishing efficacy, predicting possible toxicity, and determining optimal administration schedules. For drugs that cannot be directly labeled, imaging studies may be of value in assessing PK indirectly, for example by following the drug’s ability to displace standard radiolabeled ligands from their receptors, or by assessing its PD effects on standard imaging biomarkers, such as the use of FDG-PET as a measure of glucose metabolism. The key question that needs to be answered for each drug development program is whether the imaging results will be worth the investment. Specific questions include What can be gained from the imaging studies and at what costs? Will they shorten the development times? Will they reduce failure testing? Can the results be readily interpreted and implemented into optimal administration schedules? How will the data be received and utilized by the regulatory agency? The invited speakers are representatives from nuclear medicine area who can introduce the audience to the most recent advances in imaging technologies, who have utilized functional imaging data in elucidating PK and PD characteristics of a number of drugs, and who have expertise in submission involving imaging studies.
Moderator
Daria Stypinski, Ph.D.
MDS Pharma Services
Use of Radioactive Metabolic Tracers in Drug Development
Steve McQuarrie, Ph.D.
University of Alberta
PET Imaging in Drug Development – Industry Perspective
Donald H. Burns, Ph.D.
Merck Research Labs