Target organ profiles in toxicity studies supporting human dosing: Does severity progress with longer duration of exposure? 

Abstract:

We have previously reported the profile of target organs (defined as organs showing histopathological changes) in rodent and non-rodent toxicity studies conducted prior to first-time-in-man (FTiM) for 77 AstraZeneca candidate drugs (CDs). Here, we test the assumption that toxicity is exacerbated by dosing duration by comparing the incidence and severity of target organ toxicities in these ≤6 week FTiM studies with those observed in subsequent subchronic/chronic (≥3 month) studies. Looking at the effect of dosing duration on severity (pathological score) and incidence (percentage of animals within the group) for the 39 CDs that met the criteria for inclusion (comparable doses between FTiM and subchronic/chronic studies), new toxicities appeared for 31 target organs but existing ones resolved for 29 target organs. Increased severity was more frequent for rodent (16 target organs) than for non-rodent (4 target organs). Most notable changes were a large increase in severity/incidence in liver and in non-rodent lung in contrast to a large decrease in severity and incidence for kidneys/ureter and for the non-rodent thymus. Overall this analysis shows that, even with continued exposure, target organ toxicities of CDs are as likely to show partial or complete recovery as they are to progress in severity.

Read more here: Roberts R; Callander R; Duffy P; Jacobsen M; Knight R; Target organ profiles in toxicity studies supporting human dosing: Does severity progress with longer duration of exposure?  (2015) Regulatory Toxicology and Pharmacology 73(3) 737-746.

By |2018-06-27T16:39:23+00:00December 1st, 2015|Toxicology, Publications|Comments Off on Target organ profiles in toxicity studies supporting human dosing: Does severity progress with longer duration of exposure? 

About the Author:

Dr Richard Knight PhD, ERT, is a Director and Co-founder of ApconiX, a preclinical toxicology and ion channel company that brings together a team of world-renowned nonclinical safety experts. Richard graduated from the University of Bradford in 1989 with a degree in Biomedical Sciences (Pharmacology) before gaining a PhD at the University of Leeds researching the role of adenosine receptors in renal function and toxicity. His research then included post-doctoral studies at University of California, Los Angeles (UCLA) into the effects of ischaemia/reperfusion injury on cardiac metabolism. Richard joined Zeneca Pharmaceuticals, Safety of Medicines Group in 1996 as a Study Director, and then Project Toxicologist across multiple therapy areas, from early discovery through to market. As Lead Toxicologist for Oncology, Richard was a member of both the Drug Safety and Metabolism, and Oncology Leadership teams with responsibility for safety across the AZ oncology portfolio. In this senior role he provided leadership and mentoring support to other project toxicologists. Richard has worked on many drug platforms over this time including small molecules, biologics, proteins and oligonucleotides and has been involved in bringing over 30 new candidate drugs into clinical trials and 5 to marketing approval.