Individual variation in response to drugs is a problem that physicians routinely face in clinical practice. Such variation can result in lack of anticipated response, serious adverse drug reactions, or unexpected drug interactions in patients receiving multiple medications. In this issue of AFP, Lynch and Price review the clinical effects of cytochrome P450 (CYP450) metabolism on drug response, adverse effects, and interactions.1
The CYP450 isoenzyme superfamily, which catalyzes the oxidation of many drugs and chemicals, has long been on physicians' radar because of its role in many drug interactions that sometimes result in serious adverse events. A new dimension to the physician's interest is the understanding of genetic variations in the common CYP450 enzymes, which can also impact drug metabolism. Genetic polymorphisms have been identified for some of the CYP450 enzyme genes, with inactivating alleles that may decrease or eliminate enzyme activity, or multiple copies of functional genes that may increase enzyme activity. Phenotypically, this may translate into differing drug metabolism rates, with potential for toxicity, lack of effectiveness, or drug interactions.
The U.S. Food and Drug Administration (FDA) recently approved the Amplichip CYP450 test (a test that detects polymorphisms of CYP2D6 and CYP2C19) for use by physicians to make personalized prescribing decisions for their patients.2,3 The availability of an FDA-approved test for identifying CYP450 polymorphisms has brought the field of pharmacogenomics to the threshold of influencing clinical practice, which brings urgency to questions about the usefulness of such testing.
Recently, the Agency for Healthcare Research and Quality published a report that evaluated the evidence supporting the use of CYP450 genotyping in treating nonpsychotic depression with selective serotonin reuptake inhibitors (SSRIs).4 Researchers reviewed the literature for evidence regarding whether testing for CYP450 polymorphisms led to improved outcomes, and whether test results were useful in medical, personal, or public health decision making. The evidence indicated the existence of tests with high sensitivity and specificity for detecting only a few of the more commonly known polymorphisms of some of the CYP450 enzymes, namely CYP2D6, CYP2C19, CYP2C8, CYP2C9, and CYP1A1.
There was mixed evidence, mainly from a series of heterogeneous studies in small samples, regarding the association between CYP450 genotypes and SSRI metabolism, effectiveness, and tolerability in the treatment of depression. There were no data regarding whether testing for CYP450 polymorphisms in adults entering SSRI treatment for depression led to improved outcomes; if testing results were useful in medical, personal, or public health decision making; or if there were harms associated with testing or subsequent management options. There also were several limitations to the quality of evidence, which would need to be considered when designing future studies of the utility of CYP450 genotyping or of any type of genetic testing in clinical practice.
CYP450 genotyping is offered to physicians on the premise that the test accurately predicts how a patient will metabolize a “probe drug,” a drug that is exclusively metabolized by a given enzyme. Several drugs, including SSRIs, are often metabolized by more than one CYP450 enzyme, which may limit the predictive value of testing for a single gene polymorphism. In the case of antidepressant effects of SSRIs, genetic factors affecting serotonin receptor proteins, membrane transporters, and signal transduction molecules have important pharmacodynamic effects.5,6 Thus, genetic factors other than pharmacokinetic factors can impact SSRI outcomes in depression, and it may be misleading to examine the effects of CYP450 polymorphisms on SSRI outcomes in isolation. Multivariable pathway analysis studies are now starting to emerge and may provide more information about SSRI treatment of depression and the proportion of risk of poor outcomes that may be attributable to a certain factor, such as CYP450 polymorphisms.7
As new genetic testing technologies are approved and made available for clinical use, it is important to emphasize that FDA approval is based on test accuracy rather than on demonstration of improved clinical outcomes. Availability of technology should ideally be paralleled by availability of evidence regarding its impact in clinical practice (through methodologically sound studies), which unfortunately has not yet happened in the case of CYP450 genotyping.