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DESCRIPTIONDrug efficacy and toxicity vary substantially across individuals. Because drugs and doses are typically adjusted, if needed, by trial and error, clinical consequences may include a prolonged time to optimal therapy. In some cases, serious adverse events may result.
Various factors may influence the variability of drug effects, including age, liver function, concomitant diseases, nutrition, smoking, and drug-drug interactions. Inherited (germline) DNA sequence variation (polymorphisms) in genes for drug metabolizing enzymes, drug receptors, drug transporters, and molecules involved in signal transduction pathways also may have major effects on the efficacy or toxicity of a drug.
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. See Pharmacogenomic and Metabolite Markers for Patients with Inflammatory Bowel Disease Treated with Azathioprine (6-MP) medical policy.
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 to a lesser degree suffer some of the consequences of poor metabolizers. Ultrarapid metabolizers are individuals with more than two alleles of active enzyme gene. There is pronounced ethnic variability in the population distribution of metabolizer types for a given CYP enzyme.
Ultrarapid metabolizers of 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, it is important to realize that 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 interaction between 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 identifying an individual’s specific CYP450 genetic polymorphisms that may be linked to increased/reduced effect (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 FDA approval but which must meet general laboratory quality standards for high complexity testing. Recently, the AmpliChip (Roche Molecular Systems, Inc.) was cleared for marketing by the FDA through the 510(k) process. The AmpliChip is a microarray consisting of many DNA sequences complementary to 2 CYP450 genes applied in microscopic quantities at ordered locations on a solid surface (chip). The AmpliChip tests the DNA from a patient’s white blood cells collected in a standard anticoagulated blood sample for 29 polymorphisms and mutations for the CYP2D6 gene and 2 polymorphisms for the CYP2C19 gene. CYP2D6 metabolizes approximately 25% of all clinically used medications (e.g., dextromethorphan, beta-blockers, antiarrhythmics, antidepressants, and morphine derivatives), including many of the most prescribed drugs). CYP2C19 metabolizes several important types of drugs including proton-pump inhibitors, diazepam, propranolol, imipramine, and amitriptyline. FDA cleared the test “based on results of a study conducted by the manufacturers of hundreds of DNA samples as well as on a broad range of supporting peer-reviewed literature.”
According to FDA labeling for AmpliChip, information about either CYP2D6 or CYP2C19 genotype may be used “as an aid to clinicians in determining therapeutic strategy and treatment doses for therapeutics that are metabolized by [either] product.” AmpliChip was cleared for marketing by the FDA for CYP2D6 testing on December 23, 2004, and for CYP2C19 testing on January 10, 2005.
POLICYCYP450 genotyping for the purpose of aiding in the choice of clopidogrel versus alternative anti-platelet agents, or in decisions on the optimal dosing for clopidogrel, may be considered medically necessary.
CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all other drugs is considered investigational. This includes, but is not limited to, CYP450 genotyping for the following applications:
POLICY EXCEPTIONSFederal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
POLICY GUIDELINESInvestigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY3/31/2005: Approved by Medical Policy Advisory Committee (MPAC)
5/11/2005: Code Reference section completed
10/11/2006: Policy reviewed, no changes
9/18/2007: Policy reviewed, no changes
06/23/2010: Policy description unchanged. Policy statement revised to state that CYP450 phenotyping may be considered medically necessary in patients with cardiovascular disease undergoing treatment with clopidogrel (Plavix) for specified reasons. Other uses remain investigational; specific indications added to the investigational policy statement. FEP verbiage added to the policy exceptions section. Deleted outdated references from the Sources section. CPT code 87999 moved from non-covered to covered.
06/22/2011: The first policy statement was corrected by changing “phenotyping” to “genotyping.”
01/09/2013: Policy statements clarified; intent unchanged. Previously stated the following: "CYP450 genotyping for CYP2C19 *2 and *3 alleles may be considered medically necessary in patients with cardiovascular disease undergoing treatment with clopidogrel (Plavix) in order to identify those who are poor metabolizers of the drug (patients with CYP2C19*2/2,*3/3, and *2/3 genotypes) and who are therefore likely to exhibit poor response to the drug. Aside from the use with clopidogrel treatment noted above and the separate policies noted above, genotyping to determine specific cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity is considered investigational." Added CPT code 81225 to the Code Reference section and deleted unlisted CPT code 87999. Added ICD-9 codes 410.00 – 410.92, 411.0, 411.1, 434.10-434.91, and 443.9 to the Code Reference section.
04/04/2014: Investigational policy statement revised to remove “dose of atomoxetine HCl (approved for treatment of attention-deficit/hyperactivity disorder)” and to add “selection and dosing of selective norepinephrine reuptake inhibitors, selection and dosing of tricyclic antidepressants, and dosing and management of antituberculosis medications."
SOURCE(S)Blue Cross Blue Shield association policy #2.04.38
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.