Genotyping to determine cytochrome p450 (CYP450) genetic polymorphisms (e.g., the AmpliChip microarray test) for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity is considered experimental/investigational and not eligible for reimbursement. The clinical value of this type of genetic testing has not been established. Prospective studies are needed to assess the benefits and potential risks of this technology in guiding drug selection and dose adjustment. A participating, preferred, or network provider may bill the member for such ineligible tests.
Procedure codes 88384-88386 – Array-based evaluation of multiple molecular probes, 11 through 500 probes – may be used to report this testing. Codes 83890-83914 may be reported when less than 11 probes are evaluated.
Description
Recent advances in molecular biology have improved the understanding of genetic factors underlying many adverse drug reactions that are responsible for many debilitating side effects and are a major cause of death following drug therapy. A significant proportion of adverse drug reactions are caused by genetic polymorphism and genetically based inter-individual differences in drug absorption, disposition, excretion or metabolism.
Pharmacogenomics is the study of how an individual's genetic inheritance affects the body's response to drugs. It may be possible to predict therapeutic failures or severe adverse drug reactions in individual patients by testing for important DNA sequence variations or polymorphisms (genotyping) in key drug-metabolizing enzymes, receptors, transporters, etc. Potentially, test results could be used to optimize drug choice and/or dose earlier for more effective therapy, avoid serious adverse effects, and decrease medical costs.
The cytochrome p450 (CYP450) family is a major subset of all drug-metabolizing enzymes; several CYP450 enzymes are involved in the metabolism of a significant proportion of currently administered drugs. Some CYP450 enzyme genes are highly polymorphic, resulting in some enzyme variants that have variable metabolic capacities among individuals, and some with little to no impact on activity. Thus, CYP450 enzyme variants constitute one important group of drug-gene interactions influencing the variability of effect of some CYP450 metabolized drugs.
Individuals with 2 copies (alleles) of the most common DNA sequence of a particular CYP450 enzyme gene are termed extensive metabolizers. Poor metabolizers lack active enzyme gene alleles and intermediate metabolizers, who have one active and one inactive enzyme gene allele, may suffer to a lesser degree some of the consequences of poor metabolizers. Ultrarapid metabolizers are individuals with more than 2 alleles of an active enzyme gene. There is pronounced ethnic variability in the population distribution of metabolizer types for a given CYP enzyme.
Ultrarapid metabolizers administered an active drug may not reach therapeutic concentrations at usual, recommended doses of active drugs, while poor metabolizers may suffer more adverse events at usual doses due to reduced metabolism and increased concentrations. Conversely, for administered prodrugs that must be converted by CYP450 enzymes into active metabolites, ultrarapid metabolizers may suffer adverse effects and poor metabolizers may not respond.
However, many drugs are metabolized to varying degrees by more than one enzyme, either within or outside of the CYP450 superfamily. In addition, interaction between different metabolizing genes, interaction of genes and environment, and interactions among different non-genetic factors also influence CYP450-specific metabolizing functions. Thus, identification of a variant in a single gene in the metabolic pathway may be insufficient in all but a small proportion of drugs to explain inter-individual differences in metabolism and consequent efficacy or toxicity.
Genetically determined variability in drug response has been traditionally addressed using a trial and error approach to prescribing and dosing, along with therapeutic drug monitoring (TDM) for drugs with a very narrow therapeutic range and/or potential serious adverse effects outside that range. However, TDM is not available for all drugs of interest, and a cautious trial and error approach can lengthen the time to achieving an effective dose.
CYP450 enzyme phenotyping (identifying metabolizer status) can be accomplished by administering a test enzyme substrate to a patient and monitoring parent substrate and metabolite concentrations over time (e.g., in urine). However, testing and interpretation are time-consuming and inconvenient; as a result, phenotyping is seldom performed.
The clinical utility of CYP450 genotyping, i.e., the likelihood that genotyping will significantly improve drug choice/dosing and consequent patient outcomes, is favored when the drug under consideration has a narrow therapeutic dose range (window), when the consequences of treatment failure are severe, and/or when serious adverse reactions are more likely in patients with gene sequence variants. Under these circumstances, genotyping may direct early selection of the most effective drug or dose, and/or avoid drugs or doses likely to cause toxicity. For example, warfarin, some neuroleptics and tricyclic antidepressants have narrow therapeutic windows and can cause serious adverse events when concentrations exceed certain limits, resulting in cautious dosing protocols. Yet the potential severity of the disease condition may call for immediate and sufficient therapy; genotyping might speed the process of achieving a therapeutic dose and avoid significant adverse events.
Diagnostic genotyping tests for some CYP450 enzymes are now available. Some tests are offered as in-house laboratory services, which do not require U.S. Food and Drug Administration (FDA) approval but which must meet general laboratory quality standards for high complexity testing. The AmpliChip® is the only FDA-approved test and was cleared through the 510(k) process. The AmpliChip is a microarray consisting of many DNA sequences complementary to 2 CYP450 genes and applied in microscopic quantities at ordered locations on a solid surface (chip). | 
