Leslie Z. Benet, PhD, Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA 94143-0912, USA

Multiple new approaches have been suggested for speeding the drug development process. Will these new approaches fail miserably as the combinatorial chemistry approach a number of years ago or will they in fact lead to faster evaluation and more successful approaches to the processes important in drug development? In this presentation I will address the potential and lack of potential of new frontiers/approaches being discussed and developed today including in silico drug discovery and development, pharmacogenomics, biomarkers, systems biology, transporters, and preclinical alternatives to animal studies. Much of our work is presented within the framework of the Biopharmaceutics Drug Disposition Classification System (BDDCS). In 2005, we noted that intestinal permeability rate can very well differentiate drugs for which the major route of elimination in humans will be by metabolic processes from those where excretion of unchanged drug in the urine and bile is the major route of elimination. However, for drugs primarily eliminated unchanged in urine and bile, it is particularly difficult to differentiate poor absorption from biliary elimination when drugs have only been dosed orally to humans. We recently proposed an in silico approach to predict this difference, which surprisingly incorporates a measure of metabolic stability to differentiate renal versus biliary excretion of drugs primarily eliminated unchanged in humans. We also have recently observed that although CNS active drugs are generally hypothesized to be those with high permeability that are not substrates for brain efflux transporters, such as P-gp and BCRP, BDDCS/BCS class 1, high permeability, extensively metabolized, high solubility compounds, will exert central CNS effects, even when they are very good substrates for these efflux transporters. Pharmacogenomics has had a marked positive effect in drug development as the basis for selecting the right drug for a patient, and although personalized medicine is frequently characterized as picking the right dose in a patient, there are very few documented examples where this is clinically beneficial, due primarily to intrapatient variability. However, this lack of relevance could also be due to the fact that further unexplained and unexplored genetic differences may exist. We recently described an unexplained racial difference in a transporter based drug interaction with statins that goes beyond the well-recognized effect of OATP uptake transporters. One of the greatest obstacles to speeding drug development is recognizing whether a biomarker used in a systems biology and/or PK/PD modeling approach is, in fact, a surrogate for the long term clinical outcome upon which drug approval will be based. That is, is the biomarker only a measure of a good therapeutic outcome resulting from drug therapy or does drug dosing to change the biomarker then result in the good therapeutic outcome. We have recently examined whether the generally recognized and accepted Emax model that applies to many diverse drugs in diverse disease states, may have subsumed within it, a general principle that could allow drug developers to solve the biomarker/surrogate dilemma. Finally, I will review the important advances is the development of artificial tissue, initially hepatic, constructs for humans and preclinical animal species that will: facilitate characterization of hepatic drug disposition for low clearance compounds where traditional hepatocyte and microsome studies are limited by time-viability constraints; allow comparison of cross-animal species and human hepatic drug disposition prior to in vivo studies; permit both qualitative and quantitative identification and evaluation of formed metabolites in preclinical species and humans; confirm IVIVC in preclinical small and large animal species, as well as in humans in terms of hepatic clearance; provide data to justify early elimination of inappropriate preclinical species; and be responsive to the concerns of society, the regulatory agencies and the industry in reducing the extent of animal testing in drug development.