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Abstract: SA-PO103

Evaluating the Nephrotoxicity of Exemplar Compounds Using a Mechanistic Model of Drug-Induced AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Gebremichael, Yeshitila, DILIsym Services, Inc., Research Triangle Park, North Carolina, United States
  • Woodhead, Jeffrey L., DILIsym Services, Inc., Research Triangle Park, North Carolina, United States
  • Hamzavi, Nader, DILIsym Services, Inc., Research Triangle Park, North Carolina, United States
  • Tallapaka, Shailendra, DILIsym Services, Inc., Research Triangle Park, North Carolina, United States
  • Siler, Scott Q., DILIsym Services, Inc., Research Triangle Park, North Carolina, United States
  • Howell, Brett A., DILIsym Services, Inc., Research Triangle Park, North Carolina, United States
Background

Drug-induced nephrotoxicity is a common source of acute kidney injury (AKI) and brings clinical complexities. Drugs cause nephrotoxicity by various mechanisms, including mitochondrial dysfunction and oxidative stress. Predicting the AKI potential and toxicity mechanisms of drugs remains a challenge. We utilized a quantitative systems toxicology (QST) model to evaluate the nephrotoxicity and underlying mechanisms of two positive (cisplatin, gentamicin) and one negative (acetaminophen) control exemplar compounds.

Methods

We employed RENAsym, a QST model of drug-induced AKI that is currently under development, to evaluate the toxicity and injury mechanisms of the exemplar compounds. RENAsym represents aspects of renal proximal tubule cells (PTCs) including cell life cycle, bioenergetics, drug-induced cell death pathways, and biomarker (αGST) responses. In vitro data from literature were utilized to parameterize the oxidative stress production and clearance of the compounds. To determine the effects of drugs on mitochondrial dysfunction, electron transport chain (ETC) inhibition mechanism was parameterized using literature in vitro data.

Results

Drug nephrotoxicity was predicted by performing simulations using a virtual human model. In the simulations, a single dose of 533 mg/m2 cisplatin resulted in 17% decline of PTC viability in 2 days. The simulations also showed a significant rise in urine aGST, a biomarker that marks PTC death. Similarly, a single dose of 3 mg/kg gentamicin showed 40% cell viability decline and high αGST elevations in 1 day. In contrast, no cell viability loss or aGST elevations were observed after multiple doses of 1 g QID (a maximum recommended dose for human) acetaminophen for over a week. In terms of injury mechanisms, simulations showed oxidative stress as the dominant mechanism for both cisplatin and gentamicin-induced toxicities.

Conclusion

Simulations predicted toxicity for two positive control compounds and no toxic response to the negative control compound, in qualitative agreement with the expected behaviors. RENAsym shows promise in providing a unique tool for drug-induced AKI prediction.

Funding

  • NIDDK Support