Genotype-guided tacrolimus dosing in African American kidney transplant recipients

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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 (AA) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AA have primarily evaluated the CYP3A5*3 variant; however, there are common nonfunctional variants in AA ( CYP3A5*6 and CYP3A5*7) which do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AA are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AA using a development and validation cohort. Time posttransplant, steroid and antiviral use, age, CYP3A5*1, *3, *6 and *7 alleles were significant towards clearance. This study is the first to develop an AA specific genotype-guided tacrolimus dosing model to personalize therapy.

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Most cited references 91

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Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.

S Hoffmeyer, Amy O. Burk, Jarinke F. H. Arnold … (2000)

To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.

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Clinical pharmacokinetics of tacrolimus.

T. Prasad, A Swaminathan, Anthony J McMichael … (1995)

Tacrolimus, a novel macrocyclic lactone with potent immunosuppressive properties, is currently available as an intravenous formulation and as a capsule for oral use, although other formulations are under investigation. Tacrolimus concentrations in biological fluids have been measured using a number of methods, which are reviewed and compared in the present article. The development of a simple, specific and sensitive assay method for measuring concentrations of tacrolimus is limited by the low absorptivity of the drug, low plasma and blood concentrations, and the presence of metabolites and other drugs which may interfere with the determination of tacrolimus concentrations. Currently, most of the pharmacokinetic data available for tacrolimus are based on an enzyme-linked immunosorbent assay method, which does not distinguish tacrolimus from its metabolites. The rate of absorption of tacrolimus is variable with peak blood or plasma concentrations being reached in 0.5 to 6 hours; approximately 25% of the oral dose is bioavailable. Tacrolimus is extensively bound to red blood cells, with a mean blood to plasma ratio of about 15; albumin and alpha 1-acid glycoprotein appear to primarily bind tacrolimus in plasma. Tacrolimus is completely metabolised prior to elimination. The mean disposition half-life is 12 hours and the total body clearance based on blood concentration is approximately 0.06 L/h/kg. The elimination of tacrolimus is decreased in the presence of liver impairment and in the presence of several drugs. Various factors that contribute to the large inter- and interindividual variability in the pharmacokinetics of tacrolimus are reviewed here. Because of this variability, the narrow therapeutic index of tacrolimus, and the potential for several drug interactions, monitoring of tacrolimus blood concentrations is useful for optimisation of therapy and dosage regimen design.

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Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus.

Jan W. Lindemans, Keith C. Heyde, Marloes Van Der Maten … (2003)

The calcineurin inhibitors cyclosporine (INN, cyclosporin) and tacrolimus have a narrow therapeutic index and show considerable interindividual variability in their pharmacokinetics. The low oral bioavailability of calcineurin inhibitors is thought to result from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A4 and CYP3A5 and the multidrug efflux pump P-glycoprotein, encoded by MDR-1. Our objective was to determine the role of genetic polymorphisms in CYP3A4, CYP3A5, and MDR-1 with respect to interindividual variability in cyclosporine and tacrolimus pharmacokinetics. Kidney transplant recipients receiving cyclosporine (n = 110) or tacrolimus (n = 64) were genotyped for CYP3A4*1B and *3, CYP3A5*3 and *6, and MDR-1 C3435T. Dose-adjusted trough levels were determined and correlated with the corresponding genotype. Tacrolimus dose-adjusted trough levels were higher in CYP3A5*3/*3 patients (n = 45) than in *1/*3 plus *1/*1 patients (n = 17), as follows: median and range, 94 (34-398) ng/mL per mg/kg versus 61 (37-163) ng/mL per mg/kg (P <.0001, Mann-Whitney test). CYP3A4*1B allele carriers (n = 10) had lower tacrolimus dose-adjusted trough levels compared with those in patients with the wild-type (*1/*1) genotype (n = 54): median and range, 57 (40-163) ng/mL per mg/kg versus 89 (34-398) ng/mL per mg/kg) (P =.003, Mann-Whitney test). No evidence was found supporting a role for the MDR-1 C3435T polymorphism in tacrolimus dose requirement. None of the polymorphisms studied correlated with cyclosporine dose-adjusted predose concentrations. As a group, patients with the CYP3A5*3/*3 genotype require less tacrolimus to reach target predose concentrations compared with CYP3A5*1 allele carriers, whereas CYP3A4*1B carriers require more tacrolimus to reach target trough concentrations compared with CYP3A4*1 homozygotes.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101083949

Journal ID (pubmed-jr-id): 22416

Journal ID (nlm-ta): Pharmacogenomics J

Journal ID (iso-abbrev): Pharmacogenomics J.

Title: The pharmacogenomics journal

ISSN (Print): 1470-269X

ISSN (Electronic): 1473-1150

Publication date Nihms-submitted: 14 November 2015

Publication date (Electronic): 15 December 2015

Publication date PMC-release: 08 July 2016

Electronic Location Identifier: 10.1038/tpj.2015.87

Affiliations

[1 ]Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN

[2 ]Department of Psychology, University of Minnesota, Minneapolis, MN

[3 ]Department of Nephrology and Chronic Disease Research Group, Minneapolis Medical Research Foundation, Hennepin County Medical Center, Minneapolis, MN

[4 ]Department of Surgery, University of Minnesota, Minneapolis, MN

[5 ]Department of Biostatistics, University of Minnesota, Minneapolis, MN

[6 ]Department of Nephrology, University of Alabama, Birmingham, AL

[7 ]Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN

Author notes

Corresponding Author: Pamala Jacobson, PharmD., Department of Experimental and Clinical Pharmacology, Weaver Densford Hall, 7-151, 308 Harvard St. SE, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, Phone 612-624-6118, Fax 612-624-4694, jacob117@ 123456umn.edu

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Manuscript ID: NIHMS735273

DOI: 10.1038/tpj.2015.87

PMC ID: 4909584

PubMed ID: 26667830

SO-VID: 320b38c5-6907-4a07-88f9-7a93ceb5a03e

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Genotype-guided tacrolimus dosing in African American kidney transplant recipients

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Dermal Microdialysis in Pharmacokinetics

Most cited references 91

Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.

Clinical pharmacokinetics of tacrolimus.

Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus.

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