WHY IS ADME SO IMPORTANT? - 2

When we discuss about a compound which eventually has a potential to become a drug – we first talk about its efficacy and safety.  

Drug has to pass through four (4) different stages in its lifetime in the body. These stages are Absorption, Distribution, Metabolism and Excretion (ADME).  Not surprisingly, these are the processes which influence efficacy and toxicity/safety profile of the compounds.

Pharmacokinetics is described as WHAT THE BODY DOES TO THE DRUG?  Therefore, we should know that the body does something to the drug, due to which the concentration of the drug in the body changes with time.  This something is correlated to stages of drug's life in the body i.e. Absorption, Distribution, Metabolism and Excretion (ADME) of the drug.  

Back in 1990’s, poor pharmacokinetics was the reason for ~40% of late stage attrition (during clinical trials).  This led to the inclusion of ADME into the drug discovery process at an early stage. 

Did integration of early ADME into drug discovery process offered a positive outcome?  Without any doubt attrition due to poor pharmacokinetics and bioavailability reduced drastically by the year 2000.

Are there any other bottlenecks to be worried about before they surface in the clinic?

Yes and the areas which are of a worry are ‘toxicology and clinical safety’.  As mentioned above, we have improved our ability to predict pharmacokinetics in man.  Now we need to improve our toxicology predictions. 

Therefore, at present in vitro and in vivo assays for toxicity testing methods are highly sought after.  

Problems of toxicity can often be avoided by making a very potent compound. This means that a larger margin of safety can be achieved.