Tacrolimus

Tacrolimus is a commonly used immunosuppressant drug prescribed after solid organ and hematopoietic stem cell transplantation. It has a narrow therapeutic window and large inter-patient pharmacokinetic variability.

• Tacrolimus is a macrolide immunosuppressant that binds to the FK binding protein 12 (FKBP12) in T lymphocytes. This complex binds with calcineurin, which leads to the inhibition of both interleukin-2 production and T lymphocyte activation.
• It is one of the most frequently prescribed immunosuppressant medicines in both adult and paediatric recipients of solid organ and hematopoietic stem cell transplantation.
• Its use is complicated by high inter-patient pharmacokinetic variability and a narrow therapeutic window. Therapeutic drug monitoring is routinely recommended.
• Tacrolimus metabolism occurs by hepatic and intestinal cytochrome P450 3A (CYP3A) enzyme isoforms (CYP3A5 and, to a lesser extent, CYP3A4).
• Blood concentrations of tacrolimus are influenced by CYP3A5 enzyme expression and function, with substantial evidence linking CYP3A5 genotype to variability in 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 with at least one functional CYP3A5 allele) have significantly lower dose-adjusted trough concentrations of tacrolimus, compared to non-expressers (those with two non-functional CYP3A5 alleles, also known as poor metabolisers). These individuals require 1.5 to two times the dose to achieve similar tacrolimus blood concentration.
• The current evidence for the usefulness of CYP3A5 genotyping to guide tacrolimus dosing is largely restricted to the effect of CYP3A5 genetic variants on pharmacokinetic parameters (tacrolimus blood concentrations). Most of this evidence is from research studies on kidney transplant patients who have been prescribed tacrolimus.
• Current evidence linking genetic variation in CYP3A5 to hard clinical outcomes in patients on tacrolimus is limited and inconsistent.
• Knowledge of a patient’s CYP3A5 genotype may be most useful when first starting tacrolimus to aid quicker attainment of therapeutic blood concentrations (in CYP3A5 expressers) before and alongside therapeutic drug monitoring.

• CYP3A5 testing is not currently available via the National Genomic Test Directory.
• Patients may present with information on their CYP3A5 genotype from other healthcare systems, clinical trials or from direct-to-consumer genomic testing (caution should be exercised when interpreting results from non-validated genomic tests).
• Both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have produced prescribing recommendations for CYP3A5 and tacrolimus.
• For further information, see Results: Patient with a known CYP3A5 genotype requiring tacrolimus.

For clinicians

• CPIC: Supplemental material: Guidelines for CYP3A5 genotype and tacrolimus dosing (PDF, 44 pages)
• NHS England: National Genomic Test Directory
• PharmGKB: Annotation of CPIC Guideline for tacrolimus and CYP3A5

References:

• Birdwell KA, Decker B, Barbarino JM and others. ‘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