Tacrolimus (Prograf) – CYP3A5
Rationale
This drug gene interaction (DGI) pertains to the interaction between the cytochrome P450 3A5 (CYP3A5) gene and tacrolimus. Tacrolimus is an immunosuppressive drug that is mainly used following allogenic organ transplant to lower the risk of organ rejection but is also used to treat glomerulonephritis and graft-vs.-host disease. Tacrolimus works by suppressing the immune system to prevent white blood cells from attacking the transplanted organ. Extensive literature indicates that patients with specific genetic differences in the CYP3A5 gene may require increased doses of tacrolimus in order to prevent acute rejection in solid organ, stem cell, and bone marrow transplants.
Information presented on this page is based on evidence provided by the Clinical Pharmacogenomics Implementation Consortium (CPIC®). CPIC provides peer-reviewed, updated, evidence-based, and freely accessible guidelines for implementing pharmacogenomic results into actionable prescribing decisions for providers. CPIC guidelines include standardized terminology and a systematic grading of evidence and clinical recommendations published in a leading journal (Clinical Pharmacology and Therapeutics).
Genetic Variant Information
The CYP3A5 gene encodes the CYP35A enzyme that is involved in the metabolism of tacrolimus. There are different CYP3A5 gene versions, or variants, that affects how well tacrolimus is metabolized. Some genetic variants result in a non-functioning or decreased functioning CYP35A enzyme, while other variants result in a normal functioning CYP35A enzyme. Everyone has two copies of the CYP3A5 gene, known as alleles. Based on both alleles, individuals are classified into different ‘metabolizer statuses’ (phenotype) depending on their genetic information (genotype).
See chart below for a description of each metabolizer status and any implications for treatment.
CYP3A5 metabolizer status (phenotype) |
Alleles (genotype) |
Implication for tacrolimus pharmacologic measures |
|---|---|---|
| Poor metabolizer (CYP3A5 nonexpresser) | TWO no-function alleles | Normal dose-adjusted tacrolimus trough concentrations and chance of achieving target concentrations expected with standard dosing. |
| Intermediate metabolizer (CYP3A5 expresser) | ONE normal function allele AND ONE no-function allele | Lower dose-adjusted tacrolimus trough concentrations and decreased chance of achieving target concentrations expected with standard dosing. |
| Normal metabolizer (CYP3A5 expresser) | TWO normal function alleles | Lower dose-adjusted tacrolimus trough concentrations and decreased chance of achieving target concentrations expected with standard dosing. |
Patient’s genetic information is reported as a diplotype and this corresponds to a phenotype (i.e. metabolizer status). To see an interpretation table assigning metabolizer status by genetic variant, click here to visit CPIC and scroll down to click and download “CYP3A5 diplotype_phenotype_Table”.
Results Interpretation
Tacrolimus is a medicine used to manage several different conditions and your genes can affect how well the drug works. CPIC updates guidelines on how to best use these genetic results to support patient care. To view dosing recommendations for tacrolimus based on CYP3A5 phenotypes, click on the most recent guideline publication on CPIC’s website and scroll down to Table 2.
Please review the FDA packet insert for additional clinical considerations such as contradictions as well as dose adjustments based on age, organ function, and drug-drug interactions.
These recommendations include the use of tacrolimus for kidney, heart, lung, and hematopoietic stem cell transplant patients in which the donor and recipient genotypes are identical.
Typically, with other CYP enzymes, normal (extensive) metabolizers do not have dose recommendations. However, in the case of CYP3A5 and tacrolimus, a CYP3A5 expresser (i.e., CYP3A5 normal metabolizer or intermediate metabolizer) are poor responders to tacrolimus and predicted to require a higher than standard recommended starting dose. While CYP3A5 nonexpresser (i.e., poor metabolizer) are predicted to be normal responders to the standard recommended starting dose.
Quality of Results
Genotyping for CYP3A5 was performed within a certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Act of 1988. This validated clinical laboratory developed test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored and the accuracy of the results is determined to be > 99%.
Supporting Evidence
This link will take you to the main page on the CPIC website relating to CYP3A5 and tacrolimus. On the site, you will find links to the main guideline publication and all supplementary information including a table that reports variant frequencies across different races/ethnic groups, a table that defines genetic variants, and a table that provides a phenotype interpretation (i.e. metabolizer status).