Chemical: Drug
tacrolimus

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Prescribing Info (9) Drug Labels (1) Clinical Annotations (63)

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Dosing Guidelines

Annotation of CPIC Guideline for tacrolimus and CYP3A5
Annotation of DPWG Guideline for tacrolimus and CYP3A5

last updated 03/15/2017

1. Annotation of CPIC Guideline for tacrolimus and CYP3A5

Summary

The CPIC dosing guideline for tacrolimus recommends increasing the starting dose by 1.5 to 2 times the recommended starting dose in patients who are CYP3A5 intermediate or extensive metabolizers, though total starting dose should not exceed 0.3 mg/kg/day. Therapeutic drug monitoring should also be used to guide dose adjustments.

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

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

Likely phenotype ^a	Genotypes	Examples of diplotypes ^b	Implications for tacrolimus pharmacologic measures	Therapeutic Recommendations ^c	Classification of recommendations ^e
Extensive metabolizer (CYP3A5 expresser)	An individual carrying two functional alleles	1/1	Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrations	Increase starting dose 1.5 to 2 times recommended starting dose ^d. Total starting dose should not exceed 0.3mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments	Strong
Intermediate metabolizer (CYP3A5 expresser)	An individual carrying one functional allele and one non-functional allele	1/3, 1/6, 1/7	Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrations	Increase starting dose 1.5 to 2 times recommended starting dose ^d. Total starting dose should not exceed 0.3mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments	Strong
Poor metabolizer (CYP3A5 non-expresser)	An individual carrying two non-functional alleles	3/3, 6/6, 7/7, 3/6, 3/7, 6/7	Higher (“normal”) dose-adjusted trough concentrations of tacrolimus and increased chance of achieving target tacrolimus concentrations	Initiate therapy with standard recommended dose. Use therapeutic drug monitoring to guide dose adjustments	Strong

^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.

last updated 08/10/2011

2. Annotation of DPWG Guideline for tacrolimus and CYP3A5

Summary

There is evidence to support an interaction between tacrolimus and CYP3A5, however, there are no dosing recommendations at this time.

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."

Genotype	Therapeutic Dose Recommendation	Level of Evidence	Clinical Relevance
CYP3A5 1/1	None	Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.	Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test.
CYP3A5 1/3	None	Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.	Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-50x109/l; severe diarrhea.

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

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1. Annotation of FDA Label for tacrolimus

Full label available at DailyMed

Genes and/or phenotypes found in this label

Colitis, Ulcerative
- Adverse reactions section
- source: PHONT
Diabetes Mellitus
- Warnings section, Adverse reactions section, Precautions section
- source: PHONT
Drug Toxicity
- Adverse reactions section
- source: PHONT
Kidney Diseases
- Warnings section, Adverse reactions section
- source: PHONT
Nephritis, Interstitial
- Adverse reactions section
- source: PHONT

Clinical Variants that meet the highest level of criteria, manually curated by PharmGKB, are shown below.

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