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Example clinical scenario

A 30-year-old man with known hypertrophic cardiomyopathy is due to be started on mavacamten by the cardiomyopathy speciality team. He has undergone CYP2C19 pharmacogenomic testing and has been found to have two loss-of-function alleles, making him a poor metaboliser.

What do you need to know?

  • Mavacamten metabolism is dependent on the hepatic CYP2C19 enzyme.
  • Patients with two loss-of-function CYP2C19 alleles have significantly decreased enzyme activity, making them CYP2C19 poor metabolisers and exposing them to higher levels of the active metabolite.
  • CYP2C19 poor metabolisers have a heightened risk of systolic dysfunction (a type A adverse drug reaction) with standard dosing of mavacamten. Because of this, the UK Medicines and Healthcare products Regulatory Agency recommends prospective genotyping of patients due to be prescribed mavacamten, and a lower starting dose (2.5mg once per day) and maximum dose (5mg once per day) in those found to be poor metabolisers (and in those whose genotype is not yet known).
  • Prevalence of CYP2C19 poor metabolisers can vary widely both within and across ancestral groups. In European ancestry it is around 2%, in East Asian ancestry it is around 13%, and in Oceanic ancestry the prevalence is around 57%.
  • All patients should be monitored for early clinical response by left ventricular outflow gradient with Valsalva manoeuvre four and eight weeks after treatment initiation.
  • The summary of product characteristics for mavacamten also advises that dose adjustment should be followed if the patient is taking concomitant medicinal products that are strong inducers or inhibitors of CYP2C19 or CYP3A4 (see table 1 in the summary of product characteristics document for a useful overview).  

What do you need to do?

  • Follow the most up-to-date summary of product characteristics for mavacamten, which advises prescribing lower starting and maximum daily doses in CYP2C19 poor metabolisers and in those whose genotype is not known.
  • Genotype all patients who require mavacamten. Where CYP2C19 genotype is not already known, there should be established pathways in place within prescribing cardiology centres to arrange CYP2C19 testing.
  • Be aware that Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, as well as some international regulators, recommend genotype-guided prescribing for other therapeutics metabolised by CYP2C19, such as clopidogrel and anti-depressants (see the resources list below).
  • Record the CYP2C19 phenotype result in the patient’s medical records and communicate it to their GP to help ensure that it will be available to other prescribers.
  • If you do make any changes to the prescription of other medications based on a patient’s CYP2C19 genotype, please make a note in their medical records.

Resources

For patients

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  • Last reviewed: 31/08/2023
  • Next review due: 31/08/2024
  • Authors: Dr Emma Magavern, Dr John McDermott
  • Reviewers: Professor Bill Newman