Results: Patient with a known CYP2C9 genotype requiring non-steroidal anti-inflammatory drugs (NSAIDs)
Genetic variants in the CYP2C9 gene can alter the metabolism and clearance of non-steroidal anti-inflammatory drugs, which can increase the risk of NSAID-related adverse drug reactions including gastrointestinal bleeding, renal damage and cardiovascular adverse events.
Example clinical scenario
A 38-year-old woman presents to her GP with musculoskeletal pain following a fall. A decision is made to prescribe a course of ibuprofen. The patient has previously undergone pharmacogenomic testing, and the results show that she is a CYP2C9 poor metaboliser. This means that she is potentially at increased risk of experiencing NSAID-related adverse effects owing to reduced drug clearance.
What do you need to know?
- The CYP2C9 gene encodes the cytochrome P450 2C9 enzyme, meaning that variants in this gene significantly alter the metabolism and clearance of NSAIDs, such as ibuprofen, flurbiprofen, celecoxib, piroxicam, tenoxicam and meloxicam.
- The CYP2C9 gene is highly variable (polymorphic), with more than 61 different alleles.
- CYP2C9 genetically predicted metaboliser phenotypes (known as CYP2C9 phenotypes) have been linked to plasma NSAID concentrations, with poor metabolisers being at potentially greatest risk of NSAID-related adverse effects due to reduced drug clearance.
- Other factors that can affect NSAID drug clearance include hepatic impairment and advanced age. Further caution should be exercised in these individuals.
What do you need to do?
- At the time of writing, there is no standardised NHS guidance on adjusting prescriptions according to CYP2C9 phenotype. However, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has outlined prescribing guidelines for those with known CYP2C9 phenotypes. The latest guidance is summarised in the tables below.
- There are currently no CPIC recommendations for CYP2C9-based dosing of aceclofenac, aspirin, diclofenac, indomethacin, nabumetone or naproxen.
- Please refer to the CPIC website for the latest, most up-to-date version of the relevant guidelines.
- Ensure that the rationale for using a CYP2C9-guided prescription is clearly stated in the medical notes and on the prescription, and is explained to the patient.
- Consider also adding the information about the CYP2C9 phenotype to the patient’s medical summary, to help ensure that it will be passed on to other prescribers (for example, in secondary care).
Table 1: Simplified CPIC guidelines for CYP2C9-guided prescribing of the NSAIDs celecoxib, flurbiprofen and ibuprofen
| Likely phenotype based on genotypes | Implication | Recommendation |
| CYP2C9 intermediate metaboliser (with activity score of 1.5) | Mildly reduced metabolism | No change to recommended starting dose. |
| CYP2C9 intermediate metaboliser (with activity score of 1) | Moderately reduced metabolism | Initiate therapy with lowest recommended starting dose. |
| CYP2C9 poor metaboliser | Significantly reduced metabolism and prolonged half-life | Initiate therapy with 25%–50% of the lowest recommended starting dose. Titrate cautiously to clinical effect or 25%–50% of the maximum recommended dose. |
Table 2: Simplified CPIC guidelines for CYP2C9-guided prescribing of the NSAID meloxicam
| Likely phenotype based on genotypes | Implication | Recommendation |
| CYP2C9 intermediate metaboliser (with activity score of 1.5) | Mildly reduced metabolism | No change to recommended starting dose. |
| CYP2C9 intermediate metaboliser (with activity score of 1) | Moderately reduced metabolism | Initiate therapy with 50% of the lowest recommended starting dose. Titrate cautiously to clinical effect or 50% of the maximum recommended dose. |
| CYP2C9 poor metaboliser | Significantly reduced metabolism and prolonged half-life | Choose an alternative therapy not primarily metabolised by CYP2C9 (such as naproxen) or choose an NSAID metabolised by CYP2C9 but with a shorter half-life (such as ibuprofen – see dosing guidance above). |
Table 3: Simplified CPIC guidelines for CYP2C9-guided prescribing of the NSAIDs piroxicam and tenoxicam
| Likely phenotype based on genotypes | Implication | Recommendation |
| CYP2C9 intermediate metaboliser (with activity score of 1.5) | Mildly reduced metabolism | No change to recommended starting dose. |
| CYP2C9 intermediate metaboliser (with activity score of 1) | Moderately reduced metabolism | Choose an alternative therapy not primarily metabolised by CYP2C9 (such as naproxen) or choose an NSAID metabolised by CYP2C9 but with a shorter half-life (such as ibuprofen – see dosing guidance above). |
| CYP2C9 poor metaboliser | Significantly reduced metabolism and prolonged half-life | Choose an alternative therapy not primarily metabolised by CYP2C9 (such as naproxen) or choose an NSAID metabolised by CYP2C9 but with a shorter half-life (such as ibuprofen – see dosing guidance above). |
These tables have been adapted from the CPIC guideline for CYP2C9 genotypes and use of NSAIDs (supplement v1.0).
Please note that we have not included CYP2C9 normal metabolisers in the tables because it is recommended that standard NSAID dosing regimens are prescribed for these patients. Similarly, there are no CPIC prescribing recommendations for CYP2C9 indeterminate metabolisers, so these are also excluded from the tables.
CYP2C9 genomic testing is not currently available on the NHS via the National Genomic Test Directory. Nevertheless, patients may present with information on their CYP2C9 genotype acquired from other healthcare systems, clinical trials or, increasingly, from direct-to-consumer testing (caution should be exercised when interpreting results from non-validated genomic tests).