A validated assay to improve prediction of nephrotoxicity
The kidney handles 25% of cardiac output and therefore is exposed to significant amounts of xenobiotics and their metabolites. As the structure of new drug molecules has changed this exposure has increased and has the potential to increase the frequency of nephrotoxicity.
Nephrotoxicity is one of the key reasons that drug programmes are halted with 5 -10% of attrition due to safety concerns caused by drug toxic effects on the kidney. It is estimated that up to 20% of hospital admissions for acquired acute kidney injury (AKI) are attributable to drug induced kidney injury.
When selecting in vitro systems to assess nephrotoxicity it is important to take into account the interplay of functional apical and basolateral transporters to ensure cells are exposed to physiologically relevant concentrations of the test drug.
As the prevalence of more polar small molecules and of large molecules (peptide, oligonucleotides) in the pipeline increases the need to assess nephrotoxicity increases as these therapeutic molecules are primarily cleared through the kidney rather than the liver
Our unique aProximate™ system
- Has been validated with a wide range of structural types and demonstrated an accuracy of 80%+ in prediction of in vivo toxicity
- Is a polarised monolayer expressing all major transporters
- Allows dosing on apical and basolateral sides
- Can compare cross species behaviour with human, rat, mouse, canine and non-human primate (NHP) systems
- 96-well format allows medium scale throughput and can provide high numbers of data points and analyses to determine relative IC50s and assist decisions on lead selection
We collaborate with our customers to design protocols investigating:
Multiple assay readouts recommended by the FDA
The aProximate™ assay expresses and measures the FDA recommended biomarkers for renal toxicity, KIM-1, NGAL and clusterin, along with TEER, LDH and ATP. These biomarkers have been selected by the FDA based on data collected that shows their accumulation in the urine of patients suffering renal damage.
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Pye K, Chung G, Armstrong L, Nicholds M, Brown C. aProximateTM as a novel, predictive model of aminoglycoside-induced nephrotoxicity. Abstracts of the 55th Congress of the European Societies of Toxicology (EUROTOX 2019) TOXICOLOGY SCIENCE PROVIDING SOLUTIONS. Toxicol Lett. 2019 Oct 15;314:S167–8.