Abstract
Tacrolimus is dependent on CYP3A5 enzyme for metabolism. Expression of the CYP3A5 enzyme is controlled by several alleles including CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5*7. African Americans (AAs) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AAs have primarily evaluated the CYP3A5*3 variant; however, there are other common nonfunctional variants in AAs (CYP3A5*6 and CYP3A5*7) that do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AAs are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AAs using a development and validation cohort. Time after transplant, steroid and antiviral use, age and CYP3A5*1, *3, *6 and *7 alleles were significant toward clearance. This study is the first to develop an AA-specific genotype-guided tacrolimus dosing model to personalize therapy.
Publication types
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Multicenter Study
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Observational Study
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Research Support, N.I.H., Extramural
MeSH terms
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Adolescent
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Adult
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Aged
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Black or African American / genetics*
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Calcineurin Inhibitors / administration & dosage*
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Calcineurin Inhibitors / adverse effects
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Calcineurin Inhibitors / pharmacokinetics
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Canada / epidemiology
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Cytochrome P-450 CYP3A / genetics*
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Cytochrome P-450 CYP3A / metabolism
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Drug Dosage Calculations*
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Female
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Gene Frequency
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Genotype
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Graft Rejection / ethnology
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Graft Rejection / immunology
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Graft Rejection / prevention & control
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Graft Survival / drug effects
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Humans
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Immunosuppressive Agents / administration & dosage*
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Immunosuppressive Agents / adverse effects
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Immunosuppressive Agents / pharmacokinetics
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Kidney Transplantation* / adverse effects
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Male
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Metabolic Clearance Rate / genetics
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Middle Aged
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Models, Genetic
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Pharmacogenetics
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Pharmacogenomic Testing
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Pharmacogenomic Variants*
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Phenotype
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Tacrolimus / administration & dosage*
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Tacrolimus / adverse effects
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Tacrolimus / pharmacokinetics
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Transplant Recipients*
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Treatment Outcome
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United States / epidemiology
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Young Adult
Substances
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Calcineurin Inhibitors
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Immunosuppressive Agents
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CYP3A5 protein, human
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Cytochrome P-450 CYP3A
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Tacrolimus