Modeling of Indinavir-Induced Crystal Nephropathy in RENAsym®

Authors: Bhargava P, Tallapaka SB, Woodhead JL
Conference: SOT
Keywords: Acute kidney injury (AKI), crystal nephropathy, Indinavir, PBPK model, QST, Quantitative Systems Toxicology (QST), RENAsym
Software: RENAsym®
Division: Quantitative Systems Pharmacology (QSP)

Background

Indinavir, a protease inhibitor used to treat patients with HIV/AIDS, is known to induce crystal nephropathy. This is predominantly due to the precipitation of Indinavir in kidney tubules because of its low solubility at tubular luminal pH (pH = 5.5 to 7), approximately 30 to 35 μg/mL. Crystals can cause injury to neighboring tubular cells and can lead to tubule obstruction or crystal nephropathy. Indinavir was modeled in RENAsym®, a quantitative systems toxicology (QST) model of acute kidney injury (AKI). RENAsym contains a sub-model representing crystal formation and subsequent toxicity. Indinavir was modeled as an exemplar compound for the validation and accuracy of the crystal nephropathy sub-model.

Methods

The crystal nephropathy model within RENAsym, including crystal dynamics and tubular injury caused by crystals, was originally parameterized to an abundance of in vivo experiments for ethylene glycol due to a lack of preclinical data for indinavir treatment. Specific precipitation dynamics for indinavir were parameterized in human using in vitro precipitation experimental results¹. A physiologically-based pharmacokinetic (PBPK) model for indinavir was constructed within GastroPlus®, and two weeks of indinavir treatment (800 mg given every 8 hours) was simulated.

Results

The predicted kidney tubule concentration-time profile was imported into RENAsym, and the RENAsym crystal nephropathy sub-model predicted a crystal aggregate size of 27 μm. A longer indinavir treatment was simulated for 6 months, and RENAsym predicted a crystal aggregate size of 71 μm. These crystal aggregate size predictions are within the literature range, which reports a crystal aggregate size range from 27 μm to 103 μm².

Conclusions

The crystal nephropathy model in RENAsym accurately predicted clinical outcomes related to indinavir-induced crystal nephropathy, which demonstrates the potential for RENAsym to predict the potential crystal nephropathy liability of future compounds.

By Pallavi Bhargava, Shailendra Tallapaka, Jeffrey L. Woodhead

Presented at Society of Toxicology (SOT) 61st Annual Meeting and ToxExpo, March 27-31, 2022