Mechanistic Analysis of Cisplatin-Induced Acute Kidney Injury Using Quantitative Systems Toxicology Modeling
Objectives: Acute kidney injury is a common side effect of cisplatin chemotherapy. There are several proposed mechanisms of cisplatin-induced acute kidney injury (AKI); however, there is little understanding of which of these mechanisms is the most likely contributor to the observed toxicity.
Methods: RENAsym, a quantitative systems toxicology (QST) model of drug-induced kidney injury, was constructed using elements of known kidney physiology. Mitochondrial toxicity and oxidative stress models were adapted to the kidney environment from DILIsym, a QST model of drug-induced liver injury. In vitro data regarding cisplatin mitochondrial toxicity and oxidative stress generation were adapted from literature sources and used as inputs into RENAsym along with a basic model of cisplatin kidney exposure.
Results: Simulations reasonably recapitulated the toxicity and dose-response observed with cisplatin in both humans and rats. In the rat, mild toxicity was predicted after a 1 mg/kg single dose and severe toxicity was predicted after a 2.5 mg/kg single dose (Figure 1), which is generally in qualitative agreement with published data (1). In the human, a decline of 17% of proximal tubule cell mass was simulated after a single dose of 533 mg/m2 body area, which is in general agreement with the glomerular filtration rate decline reported in the literature (2). In both species, oxidative stress was shown to be the primary mechanism involved in the simulated toxicity.
Conclusions: RENAsym was used to predict the renal toxicity of cisplatin, and to suggest that cisplatin injury is primarily due to oxidative stress. QST modeling shows promise for being both a predictive and descriptive tool for drug-induced kidney injury.
By Jeffrey L. Woodhead, Shailendra Tallapaka, Yeshitila Gebremichael, Scott Q. Siler, Brett A. Howell
Tenth Annual American Conference on Pharmacometrics (ACoP) Annual Meeting: October 19-22, 2019, Orlando, FL