Whole-Body Autoradiography (QWBA)
QPS supports a wide range of studies for drug development, including quantitative whole-body autoradiography (QWBA) studies, which are conducted by our DMPK research team.
QWBA is a technique employed by researchers to determine the visual location and tissue distribution of radiolabeled compounds in various organs and tissues in the preclinical species. QWBA can be performed separately or combined with radiolabeled mass balance (MB) and plasma pharmacokinetic (PK) studies to provide high-resolution, quantitative data that can be used to characterize drug absorption, distribution, metabolism, and excretion (ADME) properties of drug candidates. QWBA is necessary to help scientists predict human exposure levels prior to a radiolabeled human AME study. This type of study is an integral component of the ADME package required for a New Drug Application (NDA) submission. Regulatory agencies require drug developers to characterize the ADME properties of prospective new drugs to ensure that patients are not exposed to dangerous levels of drugs or drug metabolites.
Performing a QWBA study can inform the following potential questions about the drug candidate of interest:
- Can this drug, or drug-related material, cross the blood-brain barrier (BBB) to penetrate the brain and spinal cord?
- Does this drug reach its intended target organ?
- Where does this drug distribute to and is there accumulation in specific tissues or organs?
- What is the tissue half-life?
- Does tissue exposure correlate with histopathological changes?
QWBA studies can produce valuable data for a variety of applications, including tissue distribution; placental/lacteal transfer; penetration of BBB, tumor, and/or testis; an assessment of melanin-binding; and, most importantly – human dosimetry calculations.
The Preparation and Process
Before a QWBA study can begin, the researchers need the following information about the drug candidate:
- The indication
- The route of administration
- The appropriate dose level, which presents no clinical signs or toxicity (i.e., no observed adverse effect level, or NOAEL)
- The clinical plan and treatment regimen
- The excretion pathway (if known) and in vitro ADME and transporter data
- The expectations of the relevant regulatory agency
To initiate a QWBA study, the researchers dose the radiolabeled compound to the animal of interest. At specified time-points post-dose (typically within 168 hours), the animal is humanely euthanized and the carcass is frozen. The carcass is then prepared in a solid block of embedding media. Next, a cryomicrotome is used to create thin sections of the whole animal carcass, and these sections are analyzed to determine where the compound is distributed in the body.
Single Dose Tissue Distribution Study
A single dose tissue distribution study yields valuable information that can be used to design toxicology and pharmacology experiments. In addition, the data produced by a single dose tissue distribution study is necessary to calculate the radioactive dose for a human AME study. For most compounds, a single dose tissue distribution study offers sufficient sensitivity and specificity regarding tissue distribution and the potential for accumulation.
Repeated dose tissue distribution studies can also be used, where necessary. Researchers determine the design and timing of repeated-dose tissue distribution studies on a case-by-case basis.
QWBA Imaging Techniques
Alternative imaging strategies for QWBA imaging are currently being developed without radiolabels (i.e., MALDI-MSI); however, the most common QWBA imaging technique is phosphor imaging. The high-resolution images yielded through phosphor imaging can be enlarged to provide more depth and detail of the distribution in key tissues and organs. In addition to providing tissue concentrations for human dosimetry prediction, which is required for a human AME study, QWBA offers unique tools for investigating tissue pharmacokinetics, efficacy, toxicology, drug delivery, and disposition.
Advantages of a Combination Mass Balance/PK/QWBA Study
QPS has proven innovative study design and executional excellence for radiolabeled studies and there are several advantages of placing your study at QPS:
- One Study Director manages the study for better information flow to the sponsor representative(s).
- One In-Life study protocol combines the intricacies of the two study components that have two distinct purposes to fully characterize the disposition of the drug candidate.
- Specific information such as entero-hepatic recirculation, involvement of drug transporters in the intestines or other tissues, retention of drug-derived components, metabolite profiling and quantification, and possibly mechanism of observed toxicity can be assessed through objective-driven study design.
- QPS helps save radiolabeled material and avoid possible degradation and re-purification by using the material in a timely manner, utilizing one formulation and one dose formulation assay.
- Cost and time savings are ensured because there is only one In-Life study set-up and report.
- Timely availability of both types of data facilitates interpretation and conclusions.
- Radiolabeled samples (urine, feces, bile, and plasma) are retained for potential metabolite identification and profiling under a separate protocol and report.
Completion of these preclinical DMPK studies, coupled with clinical PK and a radiolabel human mass balance and metabolite profiling study, will provide an ADME data package with exceptional scientific integrity and quality that will fully support a range of regulatory submissions.
Deborah J. Watson, Ph.D.