Quantitative whole-body autoradiography in the pharmaceutical industry: Survey results on study design, methods, and regulatory compliance

Abstract

Introduction: Quantitative whole-body autoradiography (QWBA) is a technique used to determine the tissue distribution of radiolabeled compounds in laboratory animals. This relatively new technique is quickly replacing wet-tissue dissection techniques, which, up to now, have been used by the pharmaceutical industry when performing tissue distribution studies to develop new drugs and to address regulatory compliance needs. In an effort to harmonize QWBA procedures across the pharmaceutical industry, the Society for Whole Body Autoradiography (SWBA) surveyed its membership to gain insight into the procedures and practices being used to perform tissue distribution studies conducted in support of drug development. Methods: The survey polled 29 respondents, who represent pharmaceutical companies in the United States, Europe, and Asia. Participants answered approximately 50 questions related to study design, applications, autoradiography methods, tissue quantitation, and regulatory compliance. Results: The survey revealed general consistencies and inconsistencies among the labs that responded. Consistencies were related to: isotope use and doses of radioactivity, number of animals per time point, exsanguination of animals, freezing methods, section thickness, tissue collection lists, section lyophilization, imaging technology, blood and calibration standards, tissues and sections sampled for quantitation, use of QWBA data for human dosimetry, and QWBA method validation. Inconsistencies were related to: number of time points used, euthanasia methods, carcass freezing time, microtome calibration, section thickness verification, sample collection, validation of commercial standards, use of background measurements during calibration, definition of limits of quantitation, reporting of extrapolated values, reexposure of section to determine low levels, computer system validation, definitions of raw data, audit trail documentation, studies performed under Good Laboratory Practices (GLP) vs. non-GLP conditions. Discussion: The survey indicated that most labs are now using QWBA to perform their tissue distribution studies and that these data have been submitted and accepted by regulatory authorities around the world. Procedures and practices involved in the design of these studies appear to vary somewhat. An important inconsistency found related to the number of time points used to determine the pharmacokinetic (PK) parameters for tissues, which may effect the reliability of these parameters for use in predicting human exposure to radioactivity during human radiolabeled studies. Survey results regarding QWBA methods indicated that there is a lot of consistency across surveyed labs; however, there are some inconsistent areas that raise regulatory compliance issues and these are related to the verification of section thickness, validation of commercial standards and their use in quantitation, definitions of limits of quantitation, and consideration of background measurements during quantitation. This survey provides autoradiographers, managers, and regulators with an important reference on the state-of-the art of QWBA and shows that the technique has gained wide acceptance across the pharmaceutical industry. However, it also shows that there are some key areas, such as inconsistencies in the procedures used for quantitation, that investigators may want to probe further to assure that the highest quality and most useful studies are performed.