Clinical Development

A. Phase 1 Trials

Phase 1 trials are designed to identify the early tolerability of new medicines, usually in healthy volunteers. At this time, the pharmacokinetics and phar-macodynamics of a medicine are determined in humans, thus forming the base of knowledge on how medicines should be dosed.

A genetic basis for drug response is not a new concept. As early as 1902, Archibald Garrod hypothesized that genetic variance in a biochemical pathway for the detoxification of a foreign substance was the cause of alcap-tonuria (Garrod, 1902). During World War II, it was noted that hemolysis related to antimalarial treatment was much more common among African American soldiers, leading to the identification of inherited variants of glucose-6-phosphate dehydrogenase (G-6-PD). It was during this time that scientists discovered that the prolonged muscle relaxation and apnea after suxamethonium in some patients was due to an inherited deficiency of a plasma cholinesterase. Peripheral neuropathy was observed in a significant number of patients treated with the antituberculosis drug isoniazid, leading to the identification of genetic differences in acetylation pathways.

The current approach to drug development has been to avoid putting compounds into development that have as their primary route of metabolism one of the polymorphic 450 enzymes, particularly P4502D6. Nevertheless, it may be better to have a drug metabolized through a pathway that is well understood and for which appropriate dosing recommendations can be made than through a pathway where the polymorphic drug-metabolizing enzymes are not as well understood. It is likely that in the future, study of subjects who are known to have polymorphisms in the drug-metabolizing enzymes will lead to accurate dosing recommendations for a wider range of patients and perhaps better drug tolerance. Furthermore, studies of drug-drug interactions should include subjects with polymorphisms of the involved drug-metabolizing enzymes.

We are likely to see this type of approach for new medicines, but we should not lose sight of the need to do similar research on existing medicines. At present, there are many potentially important developments in pharmacogenetic research that have not made their way into clinical practice because translational studies have not been included. Although funding for the National Institutes of Health (NIH) has increased significantly over the past 10 years, the research needed to take basic science discoveries into clinical applications has not kept up. It is this research, funded by the Health Resources and Services Administration (HRSA) and the Agency for Healthcare Research and Quality (AHRQ), that is critical to implementation of pharmacogenetics into clinical practice.

Most of the work involving pharmacogenetics of drug-metabolizing enzymes is in the investigational stage, but one test has made it into clinical practice. The thiopurine methyltransferase (TMPT) test identifies polymorphisms in the gene for the enzyme responsible for metabolism of thiopurine and other immunosuppressive drugs used to treat leukemia and other diseases (Weinshilboum, 2001). If patients have two copies of one of the polymorphisms of the gene that decrease activity, they are at risk for serious dose-related side effects, such as bone marrow suppression and even death. Carrying even one copy of the polymorphism can put patients at risk for increased side effects. At the Mayo Clinic, Memorial Sloan-Kettering, and other medical centers, genotyping of patients before treatment ensures that the appropriate dose is prescribed and patients recover from their cancer and are not harmed by their treatment.

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