Azathioprine – enzyme testing now advisable
Azathioprine – enzyme testing now advisable
A fairly recent development in the UK is the use of blood tests to determine the optimum dose of azathioprine, or whether to avoid it altogether. This also applies to the closely related drugs mercaptopurine and tioguanine. Azathioprine is often prescribed for ulcerative colitis, Crohn’s disease, severe eczema, rheumatoid arthritis and some other autoimmune conditions.
The action of an enzyme, thiopurine methyltransferase (TPMT), means that in some cases there is less azathioprine available to be converted to the active form. The activity of the enzyme in individuals varies considerably according to a range of inherited genetic factors.
This variation (genetic polymorphism) explains why even small doses are highly toxic in some people with low levels of TPMT while others tolerate relatively high doses.
The main toxic effects of excess azathioprine activity are severe anaemia and myelosuppression (dangerously low white blood cell counts). TPMT polymorphism that results in relatively decreased enzyme activity affects approximately five to 10 per cent of the general population who thus require lower doses. In up to one in 300 patients TPMT is absent, so azathioprine should be avoided.
Measuring TPMT activity using a blood test is now recommended to identify these patients prior to commencing therapy, with the BNF giving recommended starting doses of azathioprine based on TPMT test results.
Gentamicin and deafness in newborns
There has been increasing interest in using a genetic test kit to establish whether a newborn baby is vulnerable to deafness if treated with gentamicin. It is known that some babies (around 0.2 per cent) have a rare mitochondrial m.1555A>G gene variant. This variation allows gentamicin to bind more strongly to the hair cells in their ears, where it becomes toxic and can lead to permanent deafness.
Deafness is a rare but well-known adverse effect of gentamicin use, and the discovery of this gene goes some way to explain this adverse effect.
The test works by detecting the m.1555A>G variant from a swab of DNA from inside a newborn baby’s cheek, with results available in under an hour. If the m.1555A>G variant is found the baby can be treated with alternative antibiotics. The National Institute for Health and Care Excellence (NICE) has provisionally approved the use of this test kit so that more information is collected to understand how effective it is.
Pharmacogenomic profiling
The growing interest in the potential for ‘pre-emptive’ screening has led to guidelines in some countries (such as the USA and the Netherlands) to support the prescribing of more than 50 medicines where PGx biomarkers are predicted to be of clinical relevance.
The NHS in England is introducing a feasibility study for conducting PGx testing prior to commencing certain drugs and is starting a primary care service pilot this year in several general practices for antidepressants, PPIs and statins, with plans for it to become a national programme if successful.
Meanwhile, in August 2022, the NHS in Tayside launched a programme to screen stroke patients who were being considered for clopidogrel treatment to find non-responders who would be at increased risk of further strokes. It is likely that this type of screening will become more commonplace in the NHS over time.
Ethics of testing, data protection
Use of PGx profiles have been criticised by some, who argue that manufacturers and sellers overstate their usefulness and are profiting from their sales at a time when the clinical benefit is unclear.
It could be argued that the value of these tests has not lived up to the initial promise; an example being hypertension where, although it is known that individuals may respond differently to various drug classes, doing genetic tests has not yet shown much benefit in improving clinical outcome by identifying responders versus non-responders.
Another issue relates to how individuals’ DNA samples are used and who ‘owns’ them. This raises concerns about data protection, confidentiality, who may get access to the DNA results, and how testing is regulated. Furthermore, these results may well convey more information than that just related to drug metabolism. An extreme example is finding genetic abnormalities that have major health implications.
Conclusion
Although there is increasing interest in the use of PGx testing, results which can be used to alter clinical decision-making and are proven to improve clinical outcome are relatively few.
Perhaps the most important role for the pharmacy team at this current time is to advise on the place of commercial PGx tests, their usefulness, suitability, and limitations. PGx is an exciting, developing field and NHS testing is becoming more common. Precision medicine will be an increasingly important aspect of prescribing in the future.