Gene:

CYP3A5

cytochrome P450, family 3, subfamily A, polypeptide 5

Annotation

This annotation is based on the CPIC® guideline for tacrolimus and CYP3A5.

July 2015

Advanced online publication March 2015

• Guidelines regarding the use of pharmacogenomic tests in dosing of tacrolimus have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).

• These guidelines are applicable to:

  • Patients undergoing kidney, heart, lung, or hematopoietic stem cell transplant.
  • Patients undergoing liver transplant where the donor and recipient CYP3A5 genotypes are identical.

• Excerpts from the 2015 tacrolimus dosing guidelines:

  • "Blood concentrations of tacrolimus are strongly influenced by CYP3A5 genotype, with substantial evidence linking CYP3A5 genotype with phenotypic variability...In kidney, heart and lung transplant patients, over 50 studies have found that individuals with the CYP3A5*1/*1 or CYP3A5*1/*3 genotype have significantly lower dose-adjusted trough concentrations of tacrolimus as compared to those with the CYP3A5*3/*3 genotype..."
  • "Those recipients with an extensive or intermediate metabolizer phenotype will generally require an increased dose of tacrolimus to achieve therapeutic drug concentrations. We recommend a dose 1.5 - 2 times higher than standard dosing, but not to exceed 0.3 mg/kg/day, followed by [therapeutic drug monitoring] given the risk of arterial vasoconstriction, hypertension and nephrotoxicity that can occur with supratherapeutic tacrolimus concentrations."

• Download and read:

  • Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 genotypes and Tacrolimus Dosing
  • 2015 Supplement
  • 2015 Tacrolimus translation table
  • CYP3A5 allele frequency table

Table 1: Dosing recommendations for tacrolimus based on CYP3A5 phenotype:

Adapted from Tables 1 and 2 of the 2015 guideline manuscript.

^a 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 non-expresser (i.e. poor metabolizer) would require the standard recommended starting dose.

^b Additional rare variants such as CYP3A5*2, *8, and *9 may be found which are of unknown functional significance. However, if a copy of *1 is present, expected phenotype would be intermediate metabolizer.

^c This recommendation includes the use of tacrolimus in kidney, heart, lung and hematopoietic stem cell transplant patients, and liver transplant patients where the donor and recipient genotypes are identical.

^d Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors (e.g., medication interactions, or hepatic function)

^e Rating scheme is described in 2015 Supplement.

Annotation

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tacrolimus based on CYP3A5 genotype [Article:21412232]. They found evidence to support an interaction between tacrolimus and CYP3A5. However, they make no dosing recommendations at this time, due to fact that "in Dutch transplantation hospitals the tacrolimus dose is titrated in response to therapeutic drug monitoring."

• *See Methods or [Article:18253145] for definition of "good quality."
• S: statistically significant difference.

Annotation

PGx information can be found in the Use in Specific Populations, Clinical Pharmacology and Clinical Studies label sections.

Excerpts from the prasugrel (Effient) label:

In healthy subjects, patients with stable atherosclerosis, and patients with ACS receiving prasugrel, there was no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of prasugrel's active metabolite or its inhibition of platelet aggregation.

12.5 Pharmacogenomics

There is no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of prasugrel's active metabolite or its inhibition of platelet aggregation.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the prasugrel (Effient) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.