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J Clin Pharmacol. 2018 Sep;58(9):1184-1195. doi: 10.1002/jcph.1118. Epub 2018 May 18.

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

Author information

1
Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA.
2
Faculty of Pharmacy, Universités Paris Descartes-Paris Diderot, Paris, France.
3
Department of Pharmaceutical Sciences, College of Pharmacy, University of New England, Portland, ME, USA.
4
Erie County Medical Center, Division of Nephrology, Department of Medicine, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
5
Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Immunosuppressive Pharmacology Research Program, Translational Pharmacology Research Core, NYS Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, NY, USA.

Abstract

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 < .05), which was faster in extensive (mean: 45.0 L/hr) and intermediate (29.5 L/hr) metabolizers than poor metabolizers (19.8 L/hr). Simulations support CYP3A5*3*6*7 genotype-based tacrolimus dosing to enhance general race-adjusted regimens, with dose increases of 1.5-fold and 2-fold, respectively, in intermediate and extensive metabolizers for comparable exposures to poor metabolizers. This model offers a novel approach to determine tacrolimus dosing adjustments that maintain comparable therapeutic exposure between black and white recipients with different CYP3A5 genotypes.

KEYWORDS:

CYP3A5 genotypes; population pharmacokinetics; race; tacrolimus

PMID:
29775201
PMCID:
PMC6105387
[Available on 2019-09-01]
DOI:
10.1002/jcph.1118

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