Since 1980, more than 30 drugs have been withdrawn because of hepatotoxicity with many others having severe restrictions placed upon their use.
As a consequence — and to help minimise any risks to patients taking their medicines — the pharma industry is concerned not to progress compounds that show any potential DILI liability.
The new Envigo DILI Assessment programme can help identify whether a drug exhibits possible risk factors associated with drug induced liver injury. The programme can be run in full, using all of its tests, or can be conducted using single assays as required.
'Envigo’s battery of in vitro tests, typically using human cells, enables our customers to determine if a compound carries a DILI liability. A compound that is negative in our in vitro testing programme is considerably derisked from one of the failure factors newly approved drugs face,' commented Guy Webber, Scientific Manager of the In Vitro and Drug-Drug Interaction Sciences Group at Envigo.
'This allows our customers to make more informed choices as to whether they should progress the compound. The derisking approach serves to increase patient safety, provides confidence to invest and aids the in/out-licensing of new drugs,' he added.
The technologies in Envigo’s new DILI assessment programme consist of three key tests — covalent binding, reactive metabolite formation and time dependent inhibition (TDI) of cytochrome (CYP) enzymes. These are fast turnaround in vitro assays with low compound usage – requiring just milligrams of material, making them ideal for early discovery research, where typically only small amounts of compound are available.
'If a compound comes up negative in these assays, we then use this data, in conjunction with other information, such as lipophilicity, transporter inhibition, structural alert analysis and likely human dose, to make an educated assessment as to whether a compound may carry a DILI liability or not,' remarked Guy Webber.
Brian Burlinson, Principal Scientist for Safety Assessment at Envigo, commented: 'Ultimately, the DILI Assessment package forms part of Envigo’s larger derisking programme for new drugs. This broader initiative, driven by the company’s Science and Technology Advisory Group (STAG), comprises DILI assessment, drug-to-drug interactions, genotoxicity and cardiotoxicity.'
'As our derisking studies can be done early on, there is time for chemists to re-examine their molecules and assess potential changes that could be made to reduce the DILI liability while maintaining efficacy. Once the molecules are re-engineered, they can then be checked again against the Envigo assays,' added Burlinson.
