Drug Development Trends Personalized Medicines

Human health is determined by the satisfaction of basic needs such as food and the avoidance of serious hazards such as trauma, environmental change, or economic disruption. In the world today, we find examples of almost all forms of social organization that have ever existed, including communities of hunter-gatherers, nomadic pastoralists, and primitive agriculturalists; unhygienic, large cities in the third world; and modern, large cities of the developed world. This variation in living conditions is associated with differing patterns of human disease around the globe (McKeown 1988) as well as with patterns that shift in a dynamic manner, creating a rather large and varied number of therapeutic targets for the pharmaceutical industry to consider.

In contrast to the dynamic and varied patterns of human disease worldwide, the pharmaceutical industry has a long history of pursuing only those limited number of human proteins (G-protein coupled receptors, ion channels, nuclear hormone receptors, proteases, kinases, integrins, and DNA processing enzymes) that make the best drug targets (Wilson et al. 2001). Even so, a high percentage of drug candidates never reach the market because adverse reactions develop in a significant percentage of individuals, while many approved drugs are effective for only a fraction of the population in which they are prescribed. This variation in drug response depends on many factors, including gender, age, genetic background, lifestyle, living conditions, and co-morbidity.

Since the 1950s, pharmacogenetic studies have systematically identified allelic variants at genetic loci for relevant drug-metabolizing enzymes and drug targets (Evans and Relling 1999). These studies suggest that genetic tests may predict an individual's response to specific drugs and thereby allow medicines to be personalized to specific genetic backgrounds. For some drugs, the geographic distribution of allelic variants helps explain the differences in drug response across populations. The frequency of genetic polymorphisms in drug-metabolizing enzymes, which contribute significantly to phenotype, may vary among populations by as much as twelve-fold. For example, between 5 percent and 10 percent of Europeans, but only 1 percent of Japanese, have loss-of-function variants at CYP2D6 (debrisoquine oxidation) that affect the metabolism of commonly used agents such as beta-blockers, codeine, and tricyclic antidepressants. Polymorphisms in drug-metabolizing enzymes can lead to acute toxic responses, unwanted drug-drug interactions, and therapeutic failure from augmented drug metabolism (Meyer and Zanger 1997). Therefore, one approach to drug development in the future may be to test candidate formulations in populations that are genetically homogenous for certain key genetic markers. Still, specific research challenges remain as to the most appropriate way to catalog human genetic variation and relate the inferred genetic structure to the drug response.

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