Methods determining phosphor imaging limits of quantitation in whole-body autoradiography rodent tissue distribution studies affect predictions of 14C human dosimetry.

INTRODUCTION

Radioluminography, or phosphor imaging, is often used in rodent quantitative whole-body autoradiography (QWBA) studies to determine the tissue distribution and pharmacokinetic (PK) parameters of new pharmaceutical entities in rodents. The rodent tissue pharmacokinetics information are then used to predict human radiation exposure to 14C or 3H during human radioisotope mass balance studies. The human dosimetry estimation can be biased by the method used to determine the lower limit of quantitation (LOQ) of the phosphor imager. A survey of autoradiographers revealed that at least five different methods are used to determine phosphor imager LOQ. The objective of this study is to compare and evaluate the human dosimetry estimates obtained by applying those five LOQ methods to a single set of WBA data.

METHODS

Five different phosphor imager LOQ determination methods were applied to a single set of QWBA rodent tissue distribution data to produce five tissue concentration time profiles. Tissue PK parameters were determined for each profile and subsequently used to calculate the 14C exposure for a proposed human 14C mass balance study.

RESULTS

A threefold difference was observed among the five predictions of human 14C exposure when the five different phosphor imager LOQ values were applied to the initial data set.

DISCUSSION

The method chosen to determine the phosphor imaging LOQ for QWBA rodent tissue distribution study could impact the human 14C exposure estimates. The end result may either under- or overestimate the 14C-tissue exposure in humans during radioisotope studies, depending on the method used to determine LOQ. We recommend two approaches to reduce the variations in the determination of rodent tissue distribution pharmacokinetics: (1) Set more sampling time points to cover the terminal phase to obtain more accurate t 1/2 and (2) use Method 3 or the small sized sampling tool of Method 5 for LOQ determinations because it is a balanced approach for both simplicity and accuracy.