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Preclinical pipeline- ADMETox

Toxicology and animal efficacy, pharmacokinetic and safety studies.

Under EMEA guidelines (2007), safety is the paramount issue in first-in-human trials as the  healthy volunteers are unlikely to derive any medical benefits. Therefore, (i) the quality of the  medical product needs to be assured in clinical use (by GMP synthesis and correct dosing)  and (ii) sufficient safety data must be presented using the most relevant animal models. A  multicentre platform capable of performing advanced toxicology and animal testing has been  created to meet the strict regulatory requirements for preclinical filing of investigational new  medicines. This will encompass six sequential stages of drug testing. The platform will perform as a  funnel capable of filtering the many thousands of compounds emerging from the physiological  screens through a series of stringent tests to yield only the very best candidates for advanced  animal testing. The innovative design, led at the early stages by an SME  specialising in HT drug toxicology testing (INNO), will allow  maximum value from identified hit compounds. One of the  reasons cited for the failure of modern HTS technologies to  generate more new approved drugs is the early focus on  potency as the major selection criterion. Often only a few of  the most potent candidates will be selected for animal  toxicology and ‘snapshot’ PK studies in small rodent models,  inevitably reducing the chances of choosing the candidate  with the best balance of efficacy, PK suitability and safety.  Here, we apply early high content toxicology and in vitro  ADME assays to remove this emphasis. Applied in HTS  assays, a detailed picture of the toxicological parameters of  compounds can be made with feedback of information to our  medicinal chemists. Compounds with good ADMETox  parameters but lacking in potency can be fed back into the  design process for potency improvements. Only compounds  showing both anti-kinetoplastid potency and excellent  ADMETox will be tested in animal models. This strategy therefore combines optimal use of  anti-parasite screening output with application of 3R guidelines on animal testing. 

Scientific programme

next previous ADMETox Sequencial preclinical drug filter