The Use of Preclinical Imaging in Drug Development
The process of developing drugs can take at least 10 years. That’s because of the lengthy research, development, and testing phases that must occur. Only after these stages are completed can the drug be manufactured for use.
The types of studies needed to move through the drug discovery/drug development process usually follows a path from in vitro bench top research, to small animal studies, further validation in larger animals perhaps including non-human primates, and finally clinical in human trials. At every step the big questions looming over all else is; drug efficacy and drug safety/toxicity. The likelihood of a drug surviving this process is very small.
Just as the drug development pathway progresses from the test tube to in-human there is a progression from basic research to drug discovery and drug development. Each of these stages has a set of questions to be answered and increasingly those questions are being answered through what we describe as an in-vivo imaging technology platform.
Just as genomics has been a transformative tool-set in understanding the genetic basis of a number of diseases, imaging is transforming the way we “see” disease processes and the way drugs work in the living animal and in humans often in real time. And therein lies a powerful characteristic of imaging – it’s ready translation from mouse to man. There are other unique characteristics of imaging and they include:
- PK and PD studies of the actual organs and tissues affected by a drug. This allows for multi-compartmental analysis. Kinetics are a lot more sophisticated and informative.
- Longitudinal Studies that mimic clinical trials. You may be surprised to learn that most preclinical testing requires cohorts of test subjects for each time point of a study. Since imaging is non-invasive or minimally invasive the same animal is imaged for each time point. This means:
- Many times fewer animals per study.
- Integrating imaging with histopathology, hematology, clinical chemistry, and more means huge leaps in the depth of data a study can now have.
Let’s define preclinical imaging and explain how imaging is used in the development of commercial drugs.
What Is Preclinical Imaging?
Preclinical imaging is the imaging of mice to non-human primates. And Imaging is a platform technology set that acquires images and derives data from the images. Those images are often 3D maps of an organ or whole animal. Sounds simple but it can quickly seem very complicated. There are some keys to imaging:
– Modality; the means to acquire images. The instrumentation or scanner used to mimic the “tricorder” is as varied as the electro-magnetic spectrum they exploit to interrogate the anatomy and molecular dynamics of test subjects.
For molecular imaging:
– Single photon emission computed tomography or SPECT (nuclear medicine, low energy gamma rays)
– Positron emission tomography or PET (nuclear medicine, high energy positron gamma rays)
– Bio-luminescent or fluorescence optical imaging (ultra violet, visible, and infrared light)
For anatomical imaging:
– Computed tomography or CT scan (X-ray)
– Magnetic resonance imaging or MRI (radiowave frequencies)
– High-frequency micro-ultrasound (microwave frequencies)
How Does This Imaging Assist in Drug Development?
Preclinical imaging is beneficial in drug development in a multitude of ways. Here’s how:
Drug efficacy studies can be streamlined and accelerated through imaging. For example, in oncology there now are a vast array of tumor models in mice and other species. Imaging can provide three important benefits;
1. Disease staging. Anatomic (CT, MRI) and functional imaging (fMRI, ultrasound perfusion analysis, FDG-PET) can assure for example that brain tumors are in fact at the same stage before testing. Often drugs are being tested unknowingly on a range of disease states and stages. A great oncology drug could be lost in the noise.
2.Longitudinal study design that reduces the error due to animal variability. The same test subject is examined over time.
3. Drug efficacy can be measured by not only anatomic changes (often misleading) but changes in function biomarkers that track the in vivo biology of the tumor and the bodies response, for example, angiogenesis using VEGFR markers.
Preclinical imaging was first applied to drug discovery and now there is a huge body of published work but imaging applied to drug development has been much slower. Ironically imaging is likely to have its greatest impact in the drug discovery space going forward. There are 2 drug discovery spaces and each has its needs and emphasis.
The first space is drug discovery as classically defined in which questions of drug pharmacokinetics, safety, and toxicity are examined in detail before clinical trials. The emphasis is not efficacy but how a drug is processed in the body and any affect on off target tissues and organs.
The clear advantage of imaging is that any part of the test subject can be examined in real time and under physiologic conditions. Drugs can be tracked if a tracer can be appended (radionuclide, fluorescence probe). Not only can the distribution of a drug be followed (does the drug pass the Blood Brain Barrier) but it’s PK including as an example binding to opioid receptors in the brain.
The second space in which preclinical imaging has a clear role is in answering critical questions arising during clinical trials.
There are many examples of a drug having adverse effects or at least indications of some unforeseen affect during clinical trials – it is why we do clinical trials. These questions are seen during Phase II and Phase III trials and must be addressed.
For obvious ethical reasons finding answers requires returning to the preclinical space. Imaging approaches uniquely serve this space. The questions tend to revolve around questions of mechanism of action (MoA) and pharmacodynamics (PD).
Beyond direct tracking of a drug its PD profile can be determined. Using functional biomarkers from metabolism (FDG), to kidney (Tc-99m MAG3) and liver function (tc-99m mebrofenin), to brain receptor occupancy (C-11-carfentanil – mu-opioid receptor, I-123 DAT – panurgic neurons in Parkinson’s, F-18 florbetapir – TAU binding in Alzheimer’s) the effect of a drug on an off-target tissue or biochemical pathway can be queried.
But MoA and PD goes beyond molecules to include cellular components. As an example, an Anti-Sense-Oligonucleotide (ASO) was found to effect platelet numbers something unrelated to the therapeutic target.
Now, it is not unusual for a drug to effect platelets but finding a way to prevent, treat, or mitigate the affect is crucial because hemostasis is critical. Imaging became the only way to physiologically confirm the MoA. In this case platelets were very carefully purified from whole blood, In-111 labeled, and returned to the non-human primate subject.
Using SPECT imaging the platelet survival time and sequestration rates and patterns over a 24-hour period and over a fifty-four-day treatment course could be seen and quantitated in control and drug treated monkeys. The results helped definitively determine an anti PF4/drug immune response as the MoA for loss of circulating platelets and demonstrated positive means of treatment.
Preclinical imaging is increasingly a technology set that is indispensable in drug discovery through drug development, and even during clinical trials. While the technology is varied and each potentially a world in its self it is entirely manageable and accessible.
You don’t need an advanced degree in nuclear physics you only need to know folks who do – we at BioLaurus as an example. Imagine the type of data you want and our job is to make it happen where technically possible.
Our specialty is creating new imaging assays to challenging new questions. Get in contact with us today.