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Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines: Tacrolimus dosage and the CYP3A5 Genotype

What are the Clinical Pharmacogenetics Implementation Consortium(CPIC)Guidelines?

In the era of personalized medicine, we are witnessing genetic tests being incorporated into routine clinical practices. However, the extent to which pharmacogenomic tests have been qq adopted has been low, majorly due to the lack of a coherent and curated set of guidelines for their practice.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has developed certain guidelines that have been endorsed by several medical societies.They are designed to assist clinicians on how to use the results from genetic tests to determine the course of drug therapy for each patient. Genotype-based drug guidelines will help clinicians understand how a patient of a specific genotype would respond to or metabolize a particular drug. This will enable them to evaluate subsequent therapeutic options and to determine the dosage strength.

The drug: Tacrolimus

Tacrolimus is an immunosuppressant drug that is prescribed after a solid organ transplantation or hematopoietic stem cell transplantation, to lower the risk of rejection.

  • It inhibits the production of interleukin 2 (IL 2), a signaling molecule of the immune system which promotes the development and proliferation of T cells and in turn in developing immunity.
  • In 1994, US Food and Drug Administration approved tacrolimus as an anti rejection medication for liver transplantation. It is also being used to treat glomerulonephritis and graft vs host disease.
  • The drug tacrolimus has a narrow therapeutic index and its metabolism varies greatly from one individual to another. This puts individuals at the risk of underexposure, when the dosage levels are not sufficient to combat rejection, or overexposure with the risk of drug toxicity.

The gene: CYP3A5

CYP3A5 belongs to the Cytochrome P450 enzyme family. The CYP3A class is particularly known to be responsible for the oxidative metabolism of the drug tacrolimus. It comprises of four genes of which only CYP3A4 and CYP3A5 are of relevance in adults. CYP3A4 and CYP3A5 have a high degree of sequence homology and substrate overlap.

Genetic variants

Variant alleles *1, *3, *6 and *7 are defined by genotypes at particular SNPs. *1 is the functional allele, in other words, individuals possessing this genotype are CYP3A5 expressers. The alleles *3, *6 or *7 are nonfunctional and can result in truncated mRNA being formed and the loss of expression of the functional protein.

Drug-Gene Relationship:

The CYP3A5 genotype and how it affects Tacrolimus dosing

The CYP3A5 genotype greatly influences how the drug tacrolimus is metabolized in the body. Hence, the concentration of tacrolimus in the blood itself is determined by the CYP3A5 genotype of the patient.

Extensive metabolizers (CYP3A5 expressers): These are individuals who carry two *1 (functional) alleles of CYP3A5. They are homozygous *1/ *1 and are capable of metabolizing high amounts of tacrolimus. Hence they require high doses of the drug to reduce the chances of rejection.

Intermediate metabolizers (CYP3A5 expressers): These individuals possess one functional (*1) allele and one non-functional (*3, *6 or *7) allele of CYP3A5. These heterozygous genotypes are also capable of metabolizing high amounts of tacrolimus and require high doses of the drug to reduce the chances of rejection.

Poor metabolizers (CYP3A5 nonexpressers): These are compound heterozygotes with both non functional alleles (*3/*3, *6/*6, *7/*7, *3/*6, *3/*7 or *6/*7 ) of CYP3A5. These individuals have higher blood concentrations of tacrolimus and can more easily attain target concentrations.

Therapeutic Recommendations

Individuals who are extensive or intermediate metabolizers will generally require an increased dose of tacrolimus, usually 1.5-2 times higher than standard dosing, but not exceeding 0.3 mg/kg/day. Therapeutic drug monitoring should be performed to guide dose adjustments.

 

CYP3A5 Phenotype

Genotypes

Pharmacological Implications

Therapeutic Recommendations

Extensive metabolizers (CYP3A5 expresser)*1/*1Lower concentration of tacrolimus.

Decreased chance of attaining target concentration

Initiate therapy with starting dose 1.5-2 times that of standard recommended dosage and monitor process frequently.
Immediate metabolizers (CYP3A5 expresser)*1/*3, *1/*6, *1/*7Lower concentration of tacrolimus.

Decreased chance of attaining target concentration

Initiate therapy with starting dose 1.5-2 times that of standard recommended dosage and monitor process frequently.
Poor metabolizers (CYP3A5 nonexpresser)*3/*3, *6/*6, *7/*7, *3/*6, *3/*7, *6/*7 Higher concentration of tacrolimus.

Increased chance of attaining target concentration

Start therapy with the standard recommended dosage and monitor process frequently.

Potential Benefits and Risks Involved

Tacrolimus dosing needs to be routinely directed by therapeutic drug monitoring in addition to CYP3A5 genotyping. Other factors such as demographic, drug–drug interactions and genetic variation affecting tacrolimus pharmacodynamics can influence dose requirements.

Additionally, there is also the possible risk of genotyping errors that could result in overexposure and toxicity.

Caveats

Tailoring doses of tacrolimus based on CYP3A5 genotypes may improve the chances of achieving target drug concentrations, but some clinical caveats need to be kept in mind- like factors such as age and concomitant drugs that can affect tacrolimus concentrations. Other genetic variants could affect the pharmacokinetics and therefore overall exposure to the drug. Pharmacodynamic variability is present from one individual to another.

References:

  1. https://cpicpgx.org/
  2. https://www.pharmgkb.org/guideline/PA166124619
  3. https://ghr.nlm.nih.gov/gene/CYP3A5

 

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James Watson
Xcode is a pioneer in personal genomics, focussed on enabling personalized preventive healthcare. We are dedicated to empowering physicians, wellness professionals and customers with the most validated, accurate and actionable genomic information to positively impact and improve their client's health and quality of life.