A Factorial Analysis of Drug and Bleeding Effects in Toxicokinetic Studies

Abstract

The ICH revised the S3A guidance allowing blood to be microsampled for toxicokinetic analysis from the main study cohorts of rats in general toxicology studies. The resulting changes in the hemogram have been examined in healthy animals but the ability to read through the data when there are toxicological changes has not been thoroughly examined in the literature. To address this, a toxicology study in Sprague Dawley rats was conducted where animals received repeated doses of saline or valproic acid by IP injection daily for 7 days. Animals in both treatment groups were unbled, serially bled (6 bleeds/animal at 0.1 ml/bleed) or compositely bled (2 bleeds/animal at 0.6 ml/bleed) on days 1 and 7 for TK analysis. No statistically significant changes in the clinical pathology were observed for either the serial bleed or composite bleed animals when compared with their respective unbled control; however, a 4%-7% decrease in erythrocyte counts following serial bleeding and a 5%-19% decrease following composite bleeding was observed. When all the clinical pathology and organ weight data were equivalence tested, both the serial bleed and composite bleed results were equivalent to their unbled controls except for the erythroid parameters in the composite bleed group. Toxicokinetic analysis of the blood samples resulted in comparable concentration-time curves, regardless of the method of blood collection. Under these study conditions, the results show blood microsamples can be collected from the core or recovery cohort of animals in a toxicology study without impacting the toxicological interpretation in rats.

Keywords: biotransformation and toxicokinetics; exposure assessment; risk assessment; safety evaluation.