De-Risking Drug Discovery Programmes Early with ADMET

Abstract

Drug attrition that occurs in late clinical development or during post-marketing is a serious economic problem in the pharmaceutical industry (1). The cost for drug approvals is approaching $1 billion USD, and the cost of advancing a compound to Phase 1 trials can reach up to $100 million USD according to the Tufts Center for the Study of Drug Development, Tufts University School of Medicine (2). The study also estimates a $37,000 USD direct out-of-pocket cost for each day a drug is in the development stage and opportunity costs of $1.1 million USD in lost revenue (2). Given these huge expenditures, substantial savings can accrue from early recognition of problems that would demonstrate a compound’s potential to succeed in development (3). The costs associated with withdrawing a drug from the market are even greater. For example, terfenadine is both a potent hERG cardial channel ligand and is metabolized by the liver enzyme Cyp3A4. Terfenadine was frequently co-administered with Cyp3A4 inhibitors ketoconazole or erythromycin (4). The consequent overload resulted in increases in plasma terfenadine to levels that caused cardiac toxicity (5) resulting in the drug to be withdrawn from the market (6) at an estimated cost of $6 billion USD. Another example is the broadspectrum antibiotic trovafloxacin, which was introduced in 1997 and soon became Pfizer’s top seller. The drug was metabolically activated in vivo and formed a highly reactive metabolite causing severe drug-induced hepatotoxicity (7). Trovafloxacin was black labeled in 1998 (8) costing Pfizer $8.5 billion USD in lawsuits (9). With the new ability to measure hERG and other important ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) parameters early in the discovery and development process, such liabilities are now recognized earlier allowing for safer analogs to be advanced to more expensive formal preclinical and clinical stages. The purpose of preclinical ADMET also referred to as early DMPK (drug metabolism and pharmacokinetics) is to reduce the risk similar to above and avoid spending scarce resources on weak lead candidates and programs. This allows drug-development resources to be focused on fewer, but more-likely-to-succeed drug candidates. In 1993, 40 % of drugs failed in clinical trials because of pharmacokinetic (PK) and bioavailability problems (10). Since then, major technological advances have occurred in molecular biology and screening to allow major aspects of ADMET to be assessed earlier during the lead-optimization stage. By