Derisking Renal Tubular Toxicity Identified During Early Compound Screening

Renal toxicity is common cause of attrition during non‐clinical development. Renal toxicity was identified in multiple series during the early toxicology studies in rodent species. The toxicity was characterized by basophilia of tubular epithelial cells and karyomegaly upon exposure to the parent molecule. Interestingly the tubular injury was restricted primarily to the S1 and S2 segments of the proximal convoluted tubules. Electron microscopic examination of tubular epithelial cells indicated mitochondrial injury as likely mechanism for tubular injury, as evidenced by mitophagy and mitochondrial swelling. We hypothesized that the segment specificity was due to interaction of the compound with transporters (OAT1) that were specifically expressed in these tubules. To test this hypothesis rat were infused with one of the major metabolite which was determined to be the cause of tubular injury alone or in combination with an OAT1 inhibitor, Probenecid. Rats infused with the major metabolite of the drug had moderate to severe tubular injury. In rats infused with major metabolites for seven days along with probenecid partial protection was observed, indicating that transporter mediated uptake was at least partially responsible for the tubular injury. Transporter facilitated tubular epithelial accumulation likely contributed to the mitochondrial injury noted upon electron microscopic examination. A role for transporters should be considered especially when the injury is segment specific and if a transporter role is confirmed there is potential to derisk successfully as evidenced by successful application of this approach with cidofovir and adefovir. Support or Funding Information All authors are employees of AbbVie. The design, study conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.