Ondansetron

Ondansetron is a potent 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist used in the treatment and prevention of chemotherapy induced, radiation-induced and post-operative nausea and vomiting. Genetic variation in CYP2D6 can affect how ondansetron is metabolised.

Ondansetron works by selectively binding to 5-HT3 receptors centrally and on vagal afferent nerve cells in the gastrointestinal tract. This blockade of 5-HT3 receptors prevents serotonin-mediated emetogenic signalling, which reduces nausea and vomiting.

Other 5-HT3 antagonists are not included in this resource, either due to the limited evidence supporting the use of CYP2D6 genotype to guide prescribing (for example, palonosetron) or because the CYP2D6 enzyme is not primarily responsible for metabolism (for example, granisetron).

• Ondansetron undergoes first-pass metabolism in the liver and is principally metabolised by hydroxylation. Hydroxylated metabolites then undergo either glucuronide conjugation or sulfation to form inactive metabolites.
• The metabolism of ondasetron is mediated by multiple CYP enzymes, including CYP3A4, CYP1A2 and CYP2D6. Variation in these enzymes can affect how quickly a drug is broken down in the body.
• There is substantial data supporting the major role of CYP2D6 in ondansetron metabolism.
• Pharmacogenomic testing for CYP2D6 variation can identify patients who are likely to experience lower plasma concentrations of ondansetron and ensure they are prescribed an alternative drug to achieve an anti-emetic effect.
• Some other 5-HT3 receptor antagonists (for example, palonsetron) are also metabolised by multiple CYP enzymes. However, granisetron is not primarily metabolised by CYP2D6.

• At the time of writing, there are currently no UK guidelines to advise when testing for CYP2D6 variation should be considered, and testing is not yet available via the National Genomic Test Directory.
• However, the summaries of product characteristics for ondansetron and the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines include the following information.
  • Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme inhibition or reduced activity of one enzyme (for example, CYP2D6 genetic deficiency) is normally compensated by other enzymes and should result in little or no significant change in overall ondansetron clearance or dose requirement.
  • CYP2D6 is a highly polymorphic gene with over 100 known allelic variants and subvariants identified, as well as significant differences in allele frequencies between ethnically diverse groups.
  • CYP2D6 is subject to deletions, duplications and/or multiplications; clinical laboratories should report copy number variants to enable identification of CYP2D6 ultra-rapid metabolisers.
  • In known CYP2D6 ultra-rapid metabolisers, higher metabolism and clearance of ondansetron results in lower plasma concentrations.
    • Importantly, a reduced antiemetic effect has been observed in these patients.
  • Dose increases for CYP2D6 ultra-rapid metabolisers are not recommended because dose adjustments have not been studied.
  • No difference in incidence of vomiting has been observed in CYP2D6 intermediate metabolisers or poor metabolisers when compared to normal metabolisers.
  • No clinical data demonstrate greater QT prolongation in CYP2D6 poor metabolisers, despite potentially elevated plasma concentrations of ondansetron.
• Although CYP2D6 testing is not currently available within the NHS, patients may present with CYP2D6 genotype results obtained from other healthcare systems, clinical trials or direct-to-consumer testing (caution should be exercised when interpreting results from non-validated genomic tests).
• For further information, see Results: Patient with a known CYP2D6 genotype requiring ondansetron.

How should CYP2D6 pharmacogenomic results be used?

The CPIC guideline for ondansetron recommends the following.

• For CYP2D6 ultra-rapid metabolisers, consider an alternative drug not predominantly metabolised by CYP2D6 (for example, granisetron).
• For CYP2D6 normal metabolisers, initiate therapy with the recommended starting dose.
• For CYP2D6 intermediate or poor metabolisers, there is insufficient evidence to demonstrate a clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

No recommendations are yet assigned to palonosetron.

• If you follow the CPIC guidelines and alter a prescription, please refer to the CPIC website to use the latest version of the relevant guideline.
• Ensure that the rationale for using a CYP2D6-guided prescription is clearly stated in the medical notes and on the prescription, and explained to the patient.
• Consider also adding the information about the CYP2D6 phenotype to the patient’s medical summary, to help ensure that it will be passed on to other prescribers (for example, in secondary care).
• As with all prescriptions informed by pharmacogenomic results, dosing should take into account other clinical factors such as medication interactions, hepatic function and renal function.

For clinicians

• British Society for Genetic Medicine and the Royal College of General Practitioners: Position statement on direct to consumer genomic testing (PDF, two pages)
• Electronic medicines compendium (emc)
• NHS England: National Genomic Test Directory
• PharmGKB: Annotation of CPIC Guideline for ondansetron and CYP2D6

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 & Therapies 2017: volume 102, issue 2, pages 213–218. DOI: 10.1002/cpt.598

For patients

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