Results: Patient with a known CYP3A5 genotype requiring tacrolimus

A 56-year-old man is due to receive a renal transplant from a living donor. He is scheduled to begin a range of anti-rejection (immunosuppressant) medicines, one of which is tacrolimus. The patient has previously undergone pharmacogenomic testing, and the results show that he is an extensive CYP3A5 metaboliser. This means that he has an increased likelihood of lower trough concentrations of tacrolimus with standard dosing.

• Tacrolimus is a commonly used immunosuppressant drug prescribed after solid organ (such as kidney and liver) and hematopoietic stem cell transplantation.
• Enzymes of the cytochrome P450 (CYP) system are responsible for the metabolism of tacrolimus – specifically the CYP3A isoforms CYP3A4 and (especially) CYP3A5.
• Blood concentrations of tacrolimus are influenced to a large extent by differences in CYP3A5 enzyme expression and function, with substantial evidence linking CYP3A5 genotypes to variability in tacrolimus trough concentrations.
• Unlike CYP3A4 and other drug-metabolising CYP enzymes, absence of functional CYP3A5 is the norm in many populations. This is particularly notable in people of European ancestry, where 80%–85% of the population are homozygous for the non-functional CYP3A5*3 allele, making them CYP3A5 poor metabolisers.
• Evidence suggests that expressers of CYP3A5 (those having at least one functional CYP3A5 allele) have significantly lower dose-adjusted trough concentrations of tacrolimus, compared to non-expressers (those having two non-functional CYP3A5 alleles, also known as poor metabolisers). These individuals require 1.5 to two times the starting dose to achieve target tacrolimus blood concentrations.
• Most evidence linking CYP3A5 genotypes to tacrolimus concentrations stems from research studies in kidney transplant patients.
• Therapeutic drug monitoring is commonly used to guide tacrolimus dosing following transplantation. CYP3A5 genotypes may be more useful when first starting tacrolimus to aid quicker attainment of therapeutic drug concentrations (in CYP3A5 expressers).
• At the time of writing, there is no standardised guidance on altering tacrolimus prescriptions according to CYP3A5 genotypes available from the NHS, the British National Formulary or the summaries of product characteristics, despite consistent evidence supporting an association between CYP3A5 genotypes and tacrolimus dose requirement.

• Both the Clinical Pharmacogenetic Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have produced evidence-based prescribing recommendations for CYP3A5 and tacrolimus (see the references list below).
• Neither guideline is for or against CYP3A5 testing in transplantation. Instead, both provide dosing recommendations that include how to use CYP3A5 genotype information if it is already known.
• The CPIC recommends that the initial dose of tacrolimus should be increased in CYP3A5 expressers. Specifically, it advises that the starting dose should be increased by 1.5 to two times, though the total starting dose should not exceed 0.3mg/kg per day.
• For CYP3A5 non-expressers (poor metabolisers), therapy should be initiated with the standard recommended dose.
• As with all pharmacogenomic results, dosing should take into account other clinical factors, such as medication interactions, hepatic function and renal function.
• If, as a prescriber, you follow the CPIC (or DPWG) guidelines and alter a prescription or dose accordingly, please refer to their website to use the latest, most up-to-date version of the relevant guideline (see the resources list below).
• Ensure that the rationale for using a CYP3A5 genotype-guided prescription is clearly stated in the patient’s medical notes and on the prescription, and is explained to the patient.
• In addition, consider adding the information about the CYP3A5 genotype-phenotype correlation to the patient’s medical summary to help ensure that it will be passed on to other prescribers (for example, in secondary care).

Genomic testing for CYP3A5 variants

• At the time of writing, CYP3A5 testing is not currently available via the National Genomic Test Directory.
• Patients may, however, present with information about their CYP3A5 genotype obtained through other healthcare systems, clinical trials or direct-to-consumer testing (caution should be exercised when interpreting results from non-validated genomic tests).

• CPIC: Guideline for tacrolimus and CYP3A5
• CPIC: Supplementary material: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing (PDF, 44 pages)
• PharmGKB: Annotation of CPIC guideline for tacrolimus and CYP3A5

References:

• Birdwell KA, Decker B, Barbarino JM, et al. ‘Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing’. Clinical Pharmacology & Therapeutics 2015: volume 98, issue 1, pages 19–24. DOI: 10.1002/cpt.113
• Brunet M, van Gelder T, Asberg A and others. ‘Therapeutic drug monitoring of tacrolimus-personalized therapy: Second consensus report’. Therapeutic Drug Monitoring 2019: volume 41, issue 3, pages 261–307. DOI: 10.1097/FTD.0000000000000640