RENAsym, a Quantitative Systems Toxicology Platform Model, Designed to Predict Drug-Induced Kidney Injury Indicates Polymyxin B and Valproate Overdose Toxicity Potential While Simultaneously Demonstrating Acetaminophen and Valproate Safety at Therape

RENAsym is a quantitative systems toxicology (QST) modeling platform designed to predict drug-induced kidney toxicity. The model includes the proximal tubule cell (PTC) life cycle, regeneration of PTCs, sodium reabsorption, nephron death, and drug-induced injury and inflammation within the proximal tubules. The mechanisms of drug-induced toxicity included are overproduction of reactive oxygen species and mitochondrial dysfunction. Inputs into the QST model include the drug's exposure in the kidney and results from in vitro toxicity assays used to parameterize the toxicity mechanisms included in the model. The QST model has a wide array of outputs including fraction of viable PTCs, fraction of viable nephrons, and serum creatinine concentration over time that allow the user to assess the extent of kidney injury induced by a drug. Polymyxin B, valproate, and acetaminophen were three compounds used to test RENAsym's ability to correctly classify compounds as either nephrotoxic or safe. The model successfully identified polymyxin B and valproate as drugs with the potential to cause kidney injury and acetaminophen as a drug that does not cause kidney injury at therapeutic levels, providing increased confidence that the model can be used to indicate kidney injury liability using in vitro inputs before dosing in clinical settings.