Pharmacogenetics refers to the impact of a specific genetic blueprint on the effectiveness and side effects of drugs. Genetic variation, i.e. from inherited gene polymorphisms, can greatly affect clinical practice by contributing to a patient’s response to a therapeutic agent, both in terms of efficacy and toxicity. Many drugs are known to be effective in less than half of patients exposed. Similarly, numerous drugs have clinically significant side effects which account for a substantial proportion of hospitalizations and discontinuations of therapy. The promise of pharmacogenomics analysis is to increase the probability that a patient will benefit from a drug with the least risk of toxicity. Overall, pharmacogenomics provides an important tool for the use of narrow therapeutic index drugs, in which predictability of a patient’s response to a drug has long been more a matter of statistics and anecdotal experience than solid science. A steadily increasing number of drugs now include pharmacogenomics information in the labeling. Approval labeling for cancer drugs and anti-infectives in particular are likely to provide pharmacogenomics-derived guidance, including identification of specific genetic determinants in a patient that are required for the drug to be indicated for use in that patient.
CYP2D6 (cytochrome P450 2D6), a highly polymorphic hepatic dealkylizing enzyme which metabolizes as many as a quarter of therapeutic drugs, can be inherited with a variety of DNA gene sequences defining the enzyme activity as normal, poor, intermediate or rapid metabolizers. Commercially available gene sequence assays can determine whether more than a dozen alleles that contribute to enzyme activity levels are normal (wild type) or variants. Such assays are used routinely to determine the likelihood of drug responsiveness in a patient, a common example being prediction of tamoxifen efficacy in the treatment of breast cancer.
A recent label change to pimozide, an oral antipsychotic agent indicated for suppression of tics in Tourette’s Disorder, represents an interesting way of determining a patient’s pharmacogenomics profile that has resulted in a data-driven label change. CYP2D6 is one of several cytochromes that metabolize pimozide, and poor pimozide metabolizers are known to have significantly increased bioavailability. Recognizing that certain concomitant medications that act as cytochrome CYP2D6 inhibitors can elevate blood levels of pimozide and increase the risk of potentially fatal cardiac events due to QTc-induced arrhythmias, it became a concern that similar risks could ensue from increased bioavailability in poor metabolizers. Label changes in September 2011 included contraindication language for concomitant administration with CYP2D6 inhibitors, and a pharmacogenomics precaution that maximal dosing be limited and dose increasing regimens be altered in poor metabolizers. Pimozide dosing recommendations for poor metabolizers are very specific, much like recommended dosing of warfarin based on CYP2D6 genotype. Unlike many other drugs in which only general warnings are provided based on pharmacogenomics status, very specific dose and dose adjustment recommendations are provided for pimozide because of its relatively narrow therapeutic index and particular risk of serious cardiac events.
Posted by Bob Roth, Vice President & Worldwide Medical Director. For more information, please contact Bob at firstname.lastname@example.org.