Results: Patient with a known CYP2D6 genotype requiring ondansetron

A 63-year-old woman is due to have a total abdominal hysterectomy and bilateral salpingo-oophorectomy procedure, and the surgeon decides to prescribe ondansetron for the prevention of post-operative nausea and vomiting. The patient has previously undergone pharmacogenomic testing as part of a clinical trial, and the results are available in the clinic. They show that she is a CYP2D6 ultra-rapid metaboliser, meaning that she is likely to have decreased exposure and a reduced response to ondansetron, leading to an increased likelihood of vomiting following treatment.

• Ondansetron is used in the treatment and prevention of chemotherapy-induced, radiation-induced and post-operative nausea and vomiting.
• Ondansetron is a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist. It binds selectively to 5-HT3 receptors centrally and to vagal afferent nerve cells in the gastrointestinal tract to reduce nausea and vomiting.
• Ondansetron is metabolised to inactive metabolites by multiple CYP enzymes, including CYP3A4, CYP1A2 and CYP2D6.
• Variants in drug metabolising enzymes can affect how quickly a drug is broken down in the body.
• There are substantial data to support a major role of CYP2D6 in the metabolism of ondansetron.
• If available, pharmacogenetic data can be used to inform the suitability of using 5-HT3 inhibitors as anti-emetics.
• Testing for CYP2D6 variants can identify patients who are likely to experience lower plasma concentrations and ensure that they are prescribed an alternative drug more likely to achieve the required anti-emetic effect.
• In CYP2D6-UMs, higher metabolism and clearance of ondansetron results in lower plasma concentrations. A decreased anti-emetic effect has been observed in this patient group.
• Dose increases for CYP2D6-UMs are not recommended because adjustments in dosage have not been studied.
• No difference in the incidence of vomiting has been observed between CYP2D6 intermediate metabolisers or poor metabolisers when compared with normal metabolisers.
• No clinical data demonstrate greater QT prolongation in CYP2D6–PMs, despite the potentially elevated plasma concentrations of ondansetron.
• Many other factors influence the pharmacological response to ondansetron, including sex, smoking status, dose, drug interactions and comorbidities.

• At the time of writing, there is no standardised NHS guidance on altering prescriptions according to CYP2D6 genotype or phenotype.
• However, the Clinical Pharmacogenetic Implementation Consortium (CPIC) has produced pharmacogenetic prescribing recommendations for ondansetron treatment. This guideline does not recommend for or against pharmacogenomic testing for ondansetron therapy; instead, it provides dosing recommendations that include how to use pharmacogenetic information if it is already known.
• If you alter any prescription based on pharmacogenomic results, you should:
  • review the latest CPIC guidelines;
  • ensure that the rationale for using a CYP2D6-guided prescription is clearly stated in the patient’s medical notes and on the prescription, and is explained to the patient; and
  • consider highlighting the CYP2D6 genotype in the patient’s medical summary to help ensure that it will be visible to other prescribers.

Genomic testing for CYP2D6 variants

• CYP2D6 testing for patients receiving 5-HT3 antagonists has not yet been considered for inclusion in the National Genomic Test Directory and is not currently funded.
• Patients may, however, present with information about their CYP2D6 genotype obtained from other healthcare systems, clinical trials or, increasingly, from direct-to-consumer genomic testing (caution should be exercised when interpreting results from non-validated genomic tests).
• Accurately assessing CYP2D6 genotype is challenging due to the presence of copy number variants and pseudogenes. This makes it particularly important to ensure that the CYP2D6 genotype is generated by an appropriately robust assay prior to clinical use.

For clinicians

• PharmGKB: Annotation of CPIC guideline for ondansetron and CYP2D6
• Royal College of General Practitioners: Position statement on direct-to-consumer testing (PDF, two pages)

References:

• Bell GC, Caudle KE, Whirl-Carrillo M and others. ‘Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and use of ondansetron and tropisetron’. Clinical Pharmacology & Therapeutics 2017: volume 102, issue 2, pages 213–218. DOI: 10.1002/cpt.598

For patients

Please note these references are provided for information only, and include details about pharmacogenetic tests that are not available on the NHS at the time of writing.

• Cincinnati Children’s Hospital: Patient education for pharmacogenetic testing
• Cincinnati Children’s Hospital: Your CYP2D6 genetic test results and what they mean (PDF, four pages)