Pharmacogenomics: Learning exercise 1

Last updated: Tuesday, March 12, 2024

This is Edward. He is a 62-year-old male and has been admitted to hospital and diagnosed with a transient ischaemic attack (TIA).

Standard care includes starting antiplatelet therapy and the first-line choice on the local formulary is clopidogrel.

He has no significant past medical history, takes no medicines and has no known allergies.

Clopidogrel is a prodrug metabolised to its active form by the CYP2C19 enzyme which has a high rate of genetic polymorphism. People classed as ‘poor metabolisers’ can’t convert clopidogrel to its active form, while those who are ‘intermediate metabolisers’ will have significantly reduced enzyme activity. Not being able to convert clopidogrel to its active form could lead to treatment failure. It is estimated that over a quarter of the UK population carry variants that reduce their activation of clopidogrel, rising to over 50% in people of South Asian ancestry.

NICE have a diagnostic guideline in development on Clopidogrel genotype testing after ischaemic stroke or transient ischaemic attack, anticipated to be published in 2024.

Clopidogrel SmPCs have more information on the effects of CYP2C19 polymorphism and the drug metabolism. This can be found in sections 4.4 Special warnings and precautions for use and 5.2 Pharmacokinetic properties. 

The hospital has access to laboratory testing for the cytochrome p450 isoenzyme CYP2C19 and Edward consents to be tested. His phenotype is reported as the diplotype *3/*9.
If you haven't already looked at the Clinical Pharmacogenetics Implementation Consortium website on the Information sources page, now would be a good time. They have a guideline for the CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update

According to the Consortium, the diplotype *3/*9 is classed as a ‘likely poor metaboliser’. For clopidogrel in ‘likely poor metabolisers’ they advise avoid if possible and consider an alternative if clinically indicated and no contraindication. Note that this advice may not reflect current UK practice. SmPCs may also have some information on which *alleles are fully- or non-functional.

Several months after his discharge from hospital Edward goes to his GP about his low mood, and he is prescribed an SSRI antidepressant. 

The first-line choice would be citalopram 20mg once daily according to the local formulary. 

As the practice pharmacist you see on the patient's record that they have been recorded as having a ‘poor metaboliser’ status for CYP2C19 following the recent hospital admission following a TIA.  

Citalopram is metabolised by CYP2C19. Reduced metabolism to less active compounds may result in higher plasma concentrations which may increase the risk of side effects.

SmPCs have information on citalopram metabolism and use in CYP2C19 poor metabolisers.

The Clinical Pharmacogenetics Implementation Consortium has a guideline on SSRI antidepressants and various CYP enzymes.

Three months later Edward is doing well, but he presents at his GP surgery with indigestion that has not responded to several, simple over-the-counter medicines. His GP issues a prescription for the proton pump inhibitor (PPI) lansoprazole 30mg once daily.

The metabolism of lansoprazole is mainly catalysed by CYP2C19. This may result in higher plasma levels in poor metabolisers of CYP2C19. The clinical significance of this is not clear, but could result in increased efficacy and/or side effects. Information can be found in SmPCs and there is a Clinical Pharmacogenetics Implementation Consortium Guideline for Proton Pump Inhibitors and CYP2C19.