Translational ADME-Tox models

By Nico Scheer, PhD

Only a small fraction of compounds entering clinical Phase I studies obtain market approval. A major reason for failure is that current preclinical models are often poorly predictive of efficacy, pharmacokinetics and clinical safety in man. Specifically, the predictability of current preclinical animal models is limited by profound interspecies differences in drug metabolism and disposition. In response, a number of academic and commercial groups including Taconic have developed humanised mouse models.

“Humanised mice can potentially be used to more accurately predict human metabolism and drug-drug interactions.”
-Nico Scheer

The transADMET^TM portfolio is the result of a joint development programme between Taconic and its partner CXR Biosciences Ltd to deliver novel mouse models that are more predictive for the absorption, distribution, metabolism, excretion and toxicity (ADMET) of a pharmaceutical or chemical compound in humans. The transADMET^TM models are a series of mouse lines that are humanised or annulled for key proteins involved in drug metabolism and disposition. These models have the potential to significantly improve the in vivo safety and efficacy evaluation of new drugs and chemical compounds by reducing the impact of species differences and thus allowing more informative decisions in the selection of the most promising candidates to take further in development. Due to this improved selection process in the preclinical development phase, it is anticipated that the transADMET^TM models will contribute to increase the currently poor success rate of getting clinical compounds into the market.

The models are categorised in three panels representing critical pathways in drug metabolism and disposition: Xenoreceptor Panel, Cytochrome P450 Panel and Drug Transporter Panel. In each of these panels, key murine genes have been exchanged for their human counterparts and the corresponding knockout controls have been generated as well. In addition to the single modified mouse lines, multiple humanised and knockout models were developed.

Specifically, humanised mice can potentially be used to more accurately predict human metabolism and drug-drug interactions compared with existing in vivo models. For example, mice humanised for cytochrome P450s can be used to screen for human-unique or human-disproportionate metabolites prior to entering the clinic. Or mice humanised for both nuclear receptors (such as PXR and CAR) and cytochrome P450s could potentially be used to predict the impact of novel inducers on recommended victim substrates such as triazolam. 

The impact of drug transporters on parameters such as biodistribution and drug-drug interactions is increasingly recognised, and may be subject to guidelines from the FDA. The use of mice humanised for key transporter proteins such as MDR1, MRP2, BCRP, OATPs etc. is generating considerable interest in the pharmaceutical industry, and Taconic has facilitated the formation of an expert panel (TEP) bringing together experts from 8 major Companies to help progress the validation of these models.

The transADMET^TM portfolio fits extremely well with the overall Taconic mission, "to provide our customers with in vivo translational products and services to increase the efficiency of life sciences, drug discovery research and safety evaluation".

BIO:

Nico Scheer is Head of the transADMET^TM portfolio at Taconic.  He is the lead molecular biologist in creating these models and directs the team (including Chairing the TEP) towards their further development and commercialisation.