Introductory Overview

CYP2D6 (Cytochrome P450, Family 2, Subfamily D, Polypeptide 6) is one of 57 cytochrome P450s, a class of metabolic enzymes found primarily in human liver cells [1].

Despite its low hepatic abundance (1–5 % of the CYP liver content), CYP2D6 accounts at least in part for the metabolism of up to 25 % of commonly prescribed drugs such as analgesics, antiarrhythmics, antidepressants, antipsychotics and others [2-4].

Major Substrates and Inhibitors for CYP2D6

 
The highly polymorphic nature of the CYP2D6 gene is a great source of variability in CYP2D6 drug substrates responses. The current phenotypic classification of CYP2D6 includes poor, intermediate, extensive or ultra-rapid metabolizers of CYP2D6 drug substrates [7]:

• Poor metabolizers have a low or no enzyme activity and are predicted by the presence of 2 non-functional alleles (activity score 0).
• Intermediate metabolizers have reduced enzymatic activity and are predicted by the presence of two reduced activity alleles, or one reduced function allele et one non-functional allele, or one functional allele and one non-functional allele (activity score 0.5-1). Based on the specific context, the phenotype may overlap with a poor metabolizer or an extensive metabolizer.
• Extensive metabolizers have normal enzymatic activity and are predicted by the presence of 2 functional alleles, or one functional allele and one reduced function allele (activity score 1-2).
• Ultra-rapid metabolizers have increased enzymatic activity, and are predicted by the presence of more than 2 functional alleles (activity score >2).

Percentage of CYP2D6 phenotypes in Caucasians

It has been estimated that predictive CYP2D6 genotyping could be beneficial for treatment of about 30–40% of CYP2D6 drug substrates (7–10% of all drugs clinically used) [7].

Prescription Guidance

Clinical Indication

General Indications

• Testing of patients subject to / with a family history of adverse drug reaction or therapeutic failure when treated with substrates of CYP2D6.
• Preemptive screening for the identification of patients at risk of treatment toxicity or inefficacy when being prescribed substrates of CYP2D6.
• Prediction of response to CYP2D6 substrates in case of co-medications with CYP2D6 inhibitors.

For Codeine treatment

• Testing of young children prior prescription of codeine for pain management
• Testing of breastfeeding mothers prior prescription of codeine for postpartum pain
• Testing of children and adults who continue to experience pain despite high doses of codeine
• Preemptive screening for the identification of patients at risk of treatment toxicity or inefficacy when being prescribed substrates of CYP2D6 [8-9].

For Tamoxifen treatment

• Testing of potential poor outcome of Tamoxifen, especially in postmenopausal women affected by breast cancer positive for estrogen receptors [10].

Risk Management & Benefits

 
The identification of poor, intermediate and ultra-rapid metabolizers is effective at reducing the risk of adverse drug reaction or poor treatment outcomes. It help the prescribing physician to make informed decision regarding drug dose and selection.

For Codeine

CYP2D6 testing allows identification of individuals at risk for codeine adverse drug reaction (over sedation, respiratory depression) and codeine non-responders.

• CYP2D6 ultra-rapid metabolizers should avoid codeine and receive analgesics which are not substrates of CYP2D6.
• CYP2D6 poor metabolizers will have no analgesic benefit and should be prescribed with a different type of analgesics [8-9].

For Tamoxifen

CYP2D6 testing allows the detection of poor metabolizers who are unlikely going to benefit from Tamoxifen treatment. Alternate treatment such as aromatase inhibitors should be prescribed in such cases [10].

Test Characteristics

Panel Composition

Our assay identifies the most common and relevant CYP2D6 variants:

Technical Details

Methodology

Multiplex polymerase chain reaction (PCR) followed by hybridization on custom-designed array (CE-IVD).

• Analytical sensitivity: >99%
• Analytical specificity: >99%

TAT

One week on average. Urgent testing is available upon request.