Development of Quantitative Systems Toxicology Model to Predict Drug Induced Acute Kidney Injury via mtDNA Depletion Pathway
Treatment of chronic viral infections like HIV, Hepatitis B etc necessitates long term administration of powerful antivirals like
nucleoside/nucleotide reverse transcriptase inhibitors ( Several NRTI’s are primarily excreted renally and have been reported to cause nephrotoxicity The observed toxicity is partially attributed to mitochondrial dysfunction caused by inhibition of mitochondrial DNA mtDNA synthesis[ 1 We are developing a quantitative systems toxicology ( model called RENAsym ® that can potentially predict drug induced acute kidney injury ( in humans and pre clinical species by leveraging in vitro mechanistic toxicity data The objective of this work is to develop a mechanistic model to represent drug induced mtDNA depletion in proximal tubular cells and subsequent downstream toxic effects in the kidney.
The mtDNA depletion model was built within the mitochondrial dysfunction sub model of RENAsym ® The current representation of kidney bioenergetics includes equations that describe mtDNA and electron transport chain ( protein turnover, and substrate uptake and utilization by mitochondria to produce ATP The model was parameterized based on human and rodent kidney bioenergetics data reported in literature A physiologically based pharmacokinetic ( model including kidney exposure of IV administered adefovir was developed in GastroPlus TM 9 7 as an input for RENAsym Toxicity parameter inputs into RENAsym for adefovir were derived from in vitro studies where changes in mtDNA content in primary human renal proximal tubule cells exposed to adefovir were measured using RT PCR[ 2
Simulations in human at 3 mg/kg QD dosing for 40 weeks predicted a 10 decrease in ATP level and minimal reduction in the
fraction of viable PTCs Sensitivity analysis indicated that a 10 25 increase in either mtDNA destruction rate or kidney concentration of adefovir would predict significant nephrotoxicity (Fig 6 which is well within the expected variability in pharmacokinetic and toxicological parameters This qualitatively agrees with clinical observation of elevated serum creatinine in 60 of patients treated with 120 mg QD adefovir for 24 weeks[ 3
A QST model of drug induced mtDNA depletion and subsequent AKI has been constructed within RENAsym ® The model reasonably predicts adefovir induced nephrotoxicity and shows promise in being a predictive tool for drug induced AKI.
Presented at ACoP 11 Virtual Conference, Nov. 9-13, 2020
By Shailendra B. Tallapaka, Nader Hamzavi, Yeshitila Gebremichael, Scott Q. Siler, Jeffrey L. Woodhead