Drug Drug Interactions (DDI) - Newcells

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An in vitro, light responsive, retinal model for accurate predictions of in vivo outcomes you can have confidence in.

aProximateTM

Kidney platform

The most advanced near-physiological high throughput kidney proximal tubule cells (PTC) model to investigate drug transport modalities in vitro.

Lung epithelia model

Lung model

A model to investigate airway physiology, viral infection, drug safety and environmental impacts on lung airway epithelia.

Sinusoid iPSC-derived Liver model

Liver model

We are developing a model of liver sinusoid derived from human induced pluripotent stem cells (iPSC).

Drug Drug Interactions (DDI)

aProximate™ platform: The most advanced near-physiological high-throughput kidney proximal tubule cells (PTC) model providing mechanistic insights and accurate in vitro predictions for Drug-Drug interactions (DDI).

Validated model: Given the key transporters expressed and the ability to evaluate cell health/nephrotoxicity in the aProximate™ platform, the effect and mechanism of drug drug interactions (DDI) can accurately be evaluated in vitro (See below). The use of such a reliable in vitro tool will help de-risk any drug discovery process.

The impact of Drug-Drug Interactions (DDIs) in PTC

Many drugs are substrates for the same renal transporter as metabolites, leading to alterations in drug or metabolite excretion or to drug accumulation in PTCs because of drug drug interactions (DDIs). Some well-understood DDIs improve drug efficacy and are common clinical practises. For example, the half-life of penicillin is extended by the co-administration of the OAT inhibitor, probenecid. Probenecid is also sometimes used to increase the concentration of antibiotics such as cefalozin in blood to make it last longer and therefore reduce cefalozin dosage over time. In contrast, other DDIs are harmful for patients. Therefore, understanding of possible DDIs and drug transport mechanism in the kidney is crucial for any new drug.

FDA guidelines

According to the FDA regulatory guidelines supporting the investigation of drug-drug interactions, new drugs should be tested in vitro to determine whether they are substrates for renal transporters OAT-1, OAT-3 or OCT-2, due to the large number of drugs known to interact with them. When new drugs are confirmed substrates for OAT-1, OAT-3 or OCT-2, additional studies may be required by the FDA.

Case study: Drug drug interactions (DDI) with aProximate™

Renal clearance of the drug probenecid is significantly reduced by the co-administration of other drugs such as parahippurate (PAH), furosemide, cidofovir or fexofenadine in vivo, indicating drug-drug interactions via renal transporters OAT-1 and OAT-3. The aProximate™ model reproduces the interaction between PAH and probecenid observed in vivo: a significant reduction of PAH basolateral to apical flux (JBA) and net flux (JNet) is measured in the presence of probenecid in aProximate™ PTCs. This observation demonstrates that aProximate™ recapitulates proximal tubule function and accurately predicts drug-drug interactions.

A reliable model to assess drug/drug interactions (DDI). In vivo renal clearance of drugs is reduced by the OAT inhibitor probecenid (top). A similar effect if observed in vitro

Newcells aProximate™ platformDe-risk your drug discovery pipeline

Accelerate your research with a reliable and consistent supply of proximal tubule cells validated for drug safety & efficacy as well and drug transporter assays. The highly predictive platform provides detailed mechanistic insights into drug handling.  
Using in vitro aProximate™ platform accelerates and de-risk drug discovery and reduces the requirement for animal experiments for investigational studies of the kidney. 

aProximate™ The most advanced near-physiological high throughput kidney proximal tubule cell (PTC) model.

Recapitulates Proximal tubule physiology

  • Expression of all key renal transporters 
  • High throughput solution for industry 
  • Outperforms competitor in vitro models 
  • FDA approved kidney biomarkers 
  • Enables mitochondrial health monitoring 

Have any questions? Check out our Frequently Asked Questions.

RESOURCES:  

In vitro models for accurate prediction of renal tubular xenobiotic transport in vivo . Vriend J. et al., Current Opinion in Toxicology, 2021, Vol 25,2021, Pages 15-22, ISSN 2468-2020,https://doi.org/10.1016/j.cotox.2020.12.001. 

Freshly isolated primary human proximal tubule cells as an in vitro model for the detection of renal tubular toxicity. Bajaj et al., Toxicology. 2020 Sep;442:152535. doi: 10.1016/j.tox.2020.152535. Epub 2020 Jul 2.  

In vitro platforms for de risking nephrotoxicity during drug development, Brown and Primrose, Drug Target Review, Sept 20200. 

Derivation of a System-Independent Ki for P-glycoprotein Mediated Digoxin Transport from System-Dependent IC50 Data. Chaudhry A, et al., Drug Metab Dispos. 2018 Mar;46(3):279-290. doi: 10.1124/dmd.117.075606. Epub 2018 Jan 9.  

Characterisation of human tubular cell monolayers as a model of proximal tubular xenobiotic handling Brown CD et al., Toxicol Appl Pharmacol. 2008 Dec 15;233(3): 428-38. doi: 10.1016/j.taap.2008.09.018. Epub 2008 Oct 1. PMID: 18930752. 

Abundance of Drug Transporters in the Human Kidney Cortex as Quantified by Quantitative Targeted Proteomics. Prasad B,. etal., Drug Metab Dispos. 2016 Dec;44(12):1920-1924. doi: 10.1124/dmd.116.072066. Epub 2016 Sep 12.  

Predictive in vitro primary proximal tubule models for understanding nephrotoxicity in drug develppment programs. Brown C., March 2020, Webinar  

Reducing compound attrition by predicting renal tubular toxicity with in vitro PTEC models. Brown C., Sept 2020, Webinar