Tacrolimus Population Pharmacokinetics and Multiple CYP3A5 Genotypes in Black and White Renal Transplant Recipients

Tacrolimus exhibits inter‐patient pharmacokinetic variability attributed to CYP3A5 isoenzymes and the efflux transporter, P‐glycoprotein. Most black renal transplant recipients require higher tacrolimus doses compared to whites to achieve similar troughs when race‐adjusted recommendations are used....

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Bibliographic Details
Published in:Journal of clinical pharmacology 2018-09, Vol.58 (9), p.1184-1195
Main Authors: Campagne, Olivia, Mager, Donald E., Brazeau, Daniel, Venuto, Rocco C., Tornatore, Kathleen M.
Format: Article
Language:English
Subjects:
Computer simulation
CYP3A5 genotypes
Demographics
Exposure
Genotype & phenotype
Genotypes
Health risk assessment
Isoenzymes
Kidney transplantation
Metabolism
Mycophenolic acid
Pharmacokinetics
population pharmacokinetics
race
Tacrolimus
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Summary:Tacrolimus exhibits inter‐patient pharmacokinetic variability attributed to CYP3A5 isoenzymes and the efflux transporter, P‐glycoprotein. Most black renal transplant recipients require higher tacrolimus doses compared to whites to achieve similar troughs when race‐adjusted recommendations are used. An established guideline provides tacrolimus genotype dosing recommendations based on CYP3A5*1(W/T) and loss of protein function variants: CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272), CYP3A5*7 (rs41303343) and may provide more comprehensive race‐adjusted dosing recommendations. Our objective was to develop a tacrolimus population pharmacokinetic model evaluating demographic, clinical, and genomic factors in stable black and white renal transplant recipients. A secondary objective investigated race‐based tacrolimus regimens and genotype‐specific dosing. Sixty‐seven recipients receiving oral tacrolimus and mycophenolic acid ≥6 months completed a 12‐hour pharmacokinetic study. CYP3A5*3,*6,*7 and ABCB1 1236C>T, 2677G>T/A, 3435C>T polymorphisms were characterized. Patients were classified as extensive, intermediate, and poor metabolizers using a novel CYP3A5*3*6*7 metabolic composite. Modeling and simulation was performed with computer software (NONMEM 7.3, ICON Development Solutions; Ellicott City, Maryland). A 2‐compartment model with first‐order elimination and absorption with lag time best described the data. The CYP3A5*3*6*7 metabolic composite was significantly associated with tacrolimus clearance (P value 
ISSN:0091-2700
1552-4604
DOI:10.1002/jcph.1118