Ondansetron (Zofran) – CYP2D6
Rationale
This drug gene interaction (DGI) pertains to the interaction between the CYP2D6 gene and ondansetron (Zofran®). Ondansetron belongs to a class of drugs known as serotonin receptor 5-HT3 antagonists and are used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, or surgery. It works by preventing serotonin from binding the 5-HT3 receptor in the brain, thus blocking the transmission of the signal that initiates vomiting. Extensive literature indicates that patients with specific genetic differences in the CYP2D6 gene may require dose adjustments of ondansetron or an alternative medication in order to achieve therapeutic benefits.
Information presented on this page is based on evidence provided by the Clinical Pharmacogenomics Implementation Consortium (CPIC®). CPIC provides peer-reviewed, updated, evidence-based, and freely accessible guidelines for implementing pharmacogenomic results into actionable prescribing decisions for providers. CPIC guidelines include standardized terminology and a systematic grading of evidence and clinical recommendations published in a leading journal (Clinical Pharmacology and Therapeutics).
Genetic Variant Information
The CYP2D6 (sounds like “sip-2-dee-6”) gene encodes an enzyme that is involved in the metabolism of ondansetron. There are different CYP2D6 gene versions, or variants, and each has a different effect on how well ondansetron is metabolized in the body. Some variants result in a non-functioning or low-functioning CYP2D6 protein while other variants result in a normal-functioning CYP2D6 protein. A duplication of variants can lead to a hyper-active CYP2D6 protein. Different ‘metabolizer statuses’ are assigned to patients depending on their genetic information (genotype).
See chart below for a description of each metabolizer status and any implications for treatment.
|
CYP2D6 metabolizer status |
Prevalence of metabolizer status (% of patients) | Variants (genotype) |
Implication for ondansetron |
| Poor metabolizer | ~5-10% | An individual carrying ONLY no-function alleles | Very limited data available for CYP2D6 poor metabolizers. |
| Intermediate metabolizer | ~2-11% | An individual carrying ONE reduced function allele and ONE no-function allele | Very limited data available for CYP2D6 intermediate metabolizers. |
| Normal metabolizer | ~77-92% | An individual carrying TWO normal function alleles OR TWO decreased function alleles OR ONE normal function with ONE no-function OR ONE normal function with ONE decreased function allele. | Normal metabolism of ondansetron. |
| Ultrarapid metabolizer | ~1-2% | An individual carrying more than two copies of functional alleles | Increased metabolism to less active compounds when compared to normal metabolizers and is associated with decreased response to ondansetron (i.e. vomiting). |
The patient’s reported genotype corresponds to a phenotype (i.e., metabolizer status). To see an interpretation table assigning metabolizer status by genetic variant, click here to visit CPIC and scroll down to click and download “CYP2D6 diplotype-phenotype table”.
Results Interpretation
Ondansetron is a medicine used to prevent nausea and vomiting, and your genes can affect how well the drug works. CPIC updates guidelines on how to best use these genetic results to support patient care and has published its current recommendations here.
Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.
The FDA recommends that no single dose of ondansetron exceed 16 mg to avoid QT interval prolongation.
Quality of Results
Genotyping for CYP2D6 was performed within a certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Act of 1988. This validated clinical laboratory developed test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored and the accuracy of the results is determined to be > 99%.
Supporting Evidence
This link will take you to the main page on the CPIC website relating to CYP2D6, ondansetron and tropisetron (not available in the United States). On the site, you will find links to the main guideline publication and all supplementary information including a table that reports variant frequencies across different races/ethnic groups, a table that defines genetic variants, and a table that provides a phenotype interpretation (i.e. metabolizer status). Additionally, examples of point of care clinical decision support can be found at the bottom of the page.
Please note that additional drugs may have CYP2D6 interactions. For more information on drug-gene interactions, please use the search feature on the CPIC website.