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 is an enzyme that is involved in the metabolism of tacrolimus. There are different CYP3A5 gene versions, or variants, and each has a different effect on how well tacrolimus is metabolized in the body. Some variants result in normal function while others function only at an intermediate or low level. See chart below for a description of each phenotype and any implications for treatment.
CYP3A5 metabolizer status |
Variants |
Implication for tacrolimus pharmacologic measures |
|---|---|---|
| Poor metabolizer (CYP3A5 nonexpresser) | An individual carrying TWO no-function alleles | Higher (“normal”) dose-adjusted trough concentrations of tacrolimus and increased chance of achieving target tacrolimus concentrations. |
| Intermediate metabolizer (CYP3A5 expresser) | An individual carrying ONE normal function allele and ONE no-function allele | Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrations. |
| Extensive (normal) metabolizer (CYP3A5 expresser) | An individual carrying TWO normal function alleles | Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrations. |
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 and has published its current recommendations here.
These recommendations include the use of tacrolimus in the kidney, heart, lung, and hematopoietic stem cell transplant patients in which the donor and recipient genotypes are identical.
Typically, with other CYP enzymes, an extensive metabolizer would be classified as a “normal” metabolizer, and therefore, the drug dose would not change based on the patient’s genotype. However, in the case of CYP3A5 and tacrolimus, a CYP3A5 expresser (i.e., CYP3A5 extensive metabolizer or intermediate metabolizer) would require a higher recommended starting dose and the CYP3A5 nonexpresser (i.e., poor metabolizer) would require the standard recommended starting dose.
Further dose adjustments or selection of alternative therapy may be necessary because of other clinical factors (e.g., medication interactions, or hepatic function).
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).