Abstract: TH-PO116
Mathematical Representation of Drug Induced Crystal Nephropathy Using a Quantitative Systems Toxicology Approach
Session Information
- AKI: Mechanisms - I
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Tallapaka, Shailendra, Simulations Plus Inc, Research Triangle Park, North Carolina, United States
- Bhargava, Pallavi, Simulations Plus Inc, Research Triangle Park, North Carolina, United States
- Koirala, Bhabuk, Janssen Research and Development LLC, Springhouse, Pennsylvania, United States
- Woodhead, Jeffrey L., Simulations Plus Inc, Research Triangle Park, North Carolina, United States
Background
Drugs may cause crystal nephropathy by precipitating within kidney tubules or inducing the precipitation of endogenous compounds. A mechanistic mathematical model of drug induced crystal nephropathy was developed within the context of RENAsym® to help de-risk drug development programs by predicting the potential of a drug to cause crystal nephropathy. RENAsym is a quantitative systems toxicology model of acute kidney injury that includes representation of proximal tubule cells, drug-induced cell death, and resultant biomarker responses. The crystal nephropathy model comprises of formation, aggregation, distribution and elimination of crystals within the kidney and the subsequent toxic effects on kidney function.
Methods
The crystal nephropathy model was developed using ethylene glycol (EG) -induced calcium oxalate (CaOx) crystal formation as an exemplar due to the amount of literature data available to inform model parameterization. The model is designed to use the physicochemical properties of a drug in combination with tubular drug concentrations to predict crystal formation. A PBPK model representing EG and its metabolites glycolic acid, glyoxalic acid, and oxalic acid was constructed using GastroPlus 9.8 to inform oxalate concentrations in the kidney tubule. Precipitation of CaOx, crystal disposition, crystal uptake by tubular cells, cell death due to crystal induced oxidative stress, and crystal clearance was then parameterized using published data in mouse and rats.
Results
The kidney tubule concentrations predicted by the PBPK model are well above the solubility limit and therefore result in crystal formation at all simulated doses. The RENAsym crystal nephropathy submodel has been parameterized to induce mild PTC injury when EG is administered at a 0.75% (w/v) in drinking water to rats. Simulations did not predict a serum creatinine increase greater than 1.5X baseline, which aligns with the data as the simulated protocol is not expected to have an appreciable effect on creatinine clearance.
Conclusion
The crystal nephropathy model in RENAsym does a reasonable job of representing EG-induced CaOx crystal formation and its nephrotoxic effects. The model shows promise in its ability to predict kidney injury due to other compounds that can precipitate in the kidney tubule, such as indinavir.
Funding
- NIDDK Support