NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation

Katherine A Barraclough, Nicole M Isbel, Katie J Lee, Troels K Bergmann, David W Johnson, Brett C McWhinney, Jacobus P J Ungerer, Scott B Campbell, Diana R Leary, Seweryn Bialasiewicz, Rebecca J Rockett, Christine E Staatz

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

BACKGROUND: Pregnane X, encoded by the gene NR112, is a nuclear receptor whose primary role is to promote the detoxification and clearance of drugs and other foreign compounds from the body.

AIM: The aim of this study was to analyze associations between NR1I2 polymorphisms, immunosuppressant drug exposure, and clinical outcomes in adult kidney transplant recipients.

METHODS: Exposures to tacrolimus, mycophenolic acid, and total and free prednisolone were estimated at month 1 posttransplant using validated multiple regression-derived limited sampling strategies.

RESULTS: In the 158 subjects studied, median (interquartile range) dose-adjusted exposure to tacrolimus was significantly higher in individuals carrying the NR1I2 8055T variant allele, when compared with exposure in wild-type individuals [20 (14, 22) μg·h/L/mg versus 15 (9, 24) μg·h/L/mg; P =0.0007]. Using multivariable logistic regression, NR1I2 8055T carrier status was independently predictive of higher dose-adjusted tacrolimus exposure (P=0.0005). Moreover, BK viremia was seen significantly more frequently in NR1I2 8055T allele carriers compared with wild-type individuals (38% vs 18%, P=0.005) and possession of the NR1I2 8055T allele imposed significantly higher odds of BK viremia (adjusted odds ratio, 2.76 [95% confidence interval, 1.33-7.73]; P=0.006). No significant difference in geometric mean peak BK viral replication titer was observed between 8055T carriers and noncarriers. No NR1I2 SNP or haplotype was significantly, independently associated with total or free prednisolone or MPA exposure.

CONCLUSIONS: These data demonstrate an impact of pregnane X receptor polymorphisms on tacrolimus pharmacokinetics. Association of the 8055T allele with BK viremia suggests clinically significant "overimmunosuppression" in individuals with this genotype.

OriginalsprogEngelsk
TidsskriftTransplantation
Vol/bind94
Udgave nummer10
Sider (fra-til)1025-1032
ISSN0041-1337
DOI
StatusUdgivet - 2012
Udgivet eksterntJa

Fingeraftryk

Tacrolimus
Kidney Transplantation
Alleles
Mycophenolic Acid
Immunosuppressive Agents
Cytoplasmic and Nuclear Receptors
Foreign Bodies
Pharmaceutical Preparations
Haplotypes
Single Nucleotide Polymorphism
Pharmacokinetics
Logistic Models
Odds Ratio
Confidence Intervals
Kidney

Emneord

  • Adult
  • BK Virus
  • Dose-Response Relationship, Drug
  • Female
  • Genotype
  • Graft Rejection
  • Haplotypes
  • Humans
  • Immunosuppressive Agents
  • Incidence
  • Kidney Transplantation
  • Logistic Models
  • Male
  • Middle Aged
  • Mycophenolic Acid
  • Polymorphism, Single Nucleotide
  • Prednisolone
  • Prognosis
  • Prospective Studies
  • Receptors, Steroid
  • Tacrolimus
  • Viremia

Citer dette

Barraclough, K. A., Isbel, N. M., Lee, K. J., Bergmann, T. K., Johnson, D. W., McWhinney, B. C., ... Staatz, C. E. (2012). NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation. Transplantation, 94(10), 1025-1032. https://doi.org/10.1097/TP.0b013e31826c3985
Barraclough, Katherine A ; Isbel, Nicole M ; Lee, Katie J ; Bergmann, Troels K ; Johnson, David W ; McWhinney, Brett C ; Ungerer, Jacobus P J ; Campbell, Scott B ; Leary, Diana R ; Bialasiewicz, Seweryn ; Rockett, Rebecca J ; Staatz, Christine E. / NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation. I: Transplantation. 2012 ; Bind 94, Nr. 10. s. 1025-1032.
@article{77f642379ebc41899993c5161d059933,
title = "NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation",
abstract = "BACKGROUND: Pregnane X, encoded by the gene NR112, is a nuclear receptor whose primary role is to promote the detoxification and clearance of drugs and other foreign compounds from the body.AIM: The aim of this study was to analyze associations between NR1I2 polymorphisms, immunosuppressant drug exposure, and clinical outcomes in adult kidney transplant recipients.METHODS: Exposures to tacrolimus, mycophenolic acid, and total and free prednisolone were estimated at month 1 posttransplant using validated multiple regression-derived limited sampling strategies.RESULTS: In the 158 subjects studied, median (interquartile range) dose-adjusted exposure to tacrolimus was significantly higher in individuals carrying the NR1I2 8055T variant allele, when compared with exposure in wild-type individuals [20 (14, 22) μg·h/L/mg versus 15 (9, 24) μg·h/L/mg; P =0.0007]. Using multivariable logistic regression, NR1I2 8055T carrier status was independently predictive of higher dose-adjusted tacrolimus exposure (P=0.0005). Moreover, BK viremia was seen significantly more frequently in NR1I2 8055T allele carriers compared with wild-type individuals (38{\%} vs 18{\%}, P=0.005) and possession of the NR1I2 8055T allele imposed significantly higher odds of BK viremia (adjusted odds ratio, 2.76 [95{\%} confidence interval, 1.33-7.73]; P=0.006). No significant difference in geometric mean peak BK viral replication titer was observed between 8055T carriers and noncarriers. No NR1I2 SNP or haplotype was significantly, independently associated with total or free prednisolone or MPA exposure.CONCLUSIONS: These data demonstrate an impact of pregnane X receptor polymorphisms on tacrolimus pharmacokinetics. Association of the 8055T allele with BK viremia suggests clinically significant {"}overimmunosuppression{"} in individuals with this genotype.",
keywords = "Adult, BK Virus, Dose-Response Relationship, Drug, Female, Genotype, Graft Rejection, Haplotypes, Humans, Immunosuppressive Agents, Incidence, Kidney Transplantation, Logistic Models, Male, Middle Aged, Mycophenolic Acid, Polymorphism, Single Nucleotide, Prednisolone, Prognosis, Prospective Studies, Receptors, Steroid, Tacrolimus, Viremia",
author = "Barraclough, {Katherine A} and Isbel, {Nicole M} and Lee, {Katie J} and Bergmann, {Troels K} and Johnson, {David W} and McWhinney, {Brett C} and Ungerer, {Jacobus P J} and Campbell, {Scott B} and Leary, {Diana R} and Seweryn Bialasiewicz and Rockett, {Rebecca J} and Staatz, {Christine E}",
year = "2012",
doi = "10.1097/TP.0b013e31826c3985",
language = "English",
volume = "94",
pages = "1025--1032",
journal = "Transplantation",
issn = "0041-1337",
publisher = "Lippincott Williams & Wilkins",
number = "10",

}

Barraclough, KA, Isbel, NM, Lee, KJ, Bergmann, TK, Johnson, DW, McWhinney, BC, Ungerer, JPJ, Campbell, SB, Leary, DR, Bialasiewicz, S, Rockett, RJ & Staatz, CE 2012, 'NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation', Transplantation, bind 94, nr. 10, s. 1025-1032. https://doi.org/10.1097/TP.0b013e31826c3985

NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation. / Barraclough, Katherine A; Isbel, Nicole M; Lee, Katie J; Bergmann, Troels K; Johnson, David W; McWhinney, Brett C; Ungerer, Jacobus P J; Campbell, Scott B; Leary, Diana R; Bialasiewicz, Seweryn; Rockett, Rebecca J; Staatz, Christine E.

I: Transplantation, Bind 94, Nr. 10, 2012, s. 1025-1032.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation

AU - Barraclough, Katherine A

AU - Isbel, Nicole M

AU - Lee, Katie J

AU - Bergmann, Troels K

AU - Johnson, David W

AU - McWhinney, Brett C

AU - Ungerer, Jacobus P J

AU - Campbell, Scott B

AU - Leary, Diana R

AU - Bialasiewicz, Seweryn

AU - Rockett, Rebecca J

AU - Staatz, Christine E

PY - 2012

Y1 - 2012

N2 - BACKGROUND: Pregnane X, encoded by the gene NR112, is a nuclear receptor whose primary role is to promote the detoxification and clearance of drugs and other foreign compounds from the body.AIM: The aim of this study was to analyze associations between NR1I2 polymorphisms, immunosuppressant drug exposure, and clinical outcomes in adult kidney transplant recipients.METHODS: Exposures to tacrolimus, mycophenolic acid, and total and free prednisolone were estimated at month 1 posttransplant using validated multiple regression-derived limited sampling strategies.RESULTS: In the 158 subjects studied, median (interquartile range) dose-adjusted exposure to tacrolimus was significantly higher in individuals carrying the NR1I2 8055T variant allele, when compared with exposure in wild-type individuals [20 (14, 22) μg·h/L/mg versus 15 (9, 24) μg·h/L/mg; P =0.0007]. Using multivariable logistic regression, NR1I2 8055T carrier status was independently predictive of higher dose-adjusted tacrolimus exposure (P=0.0005). Moreover, BK viremia was seen significantly more frequently in NR1I2 8055T allele carriers compared with wild-type individuals (38% vs 18%, P=0.005) and possession of the NR1I2 8055T allele imposed significantly higher odds of BK viremia (adjusted odds ratio, 2.76 [95% confidence interval, 1.33-7.73]; P=0.006). No significant difference in geometric mean peak BK viral replication titer was observed between 8055T carriers and noncarriers. No NR1I2 SNP or haplotype was significantly, independently associated with total or free prednisolone or MPA exposure.CONCLUSIONS: These data demonstrate an impact of pregnane X receptor polymorphisms on tacrolimus pharmacokinetics. Association of the 8055T allele with BK viremia suggests clinically significant "overimmunosuppression" in individuals with this genotype.

AB - BACKGROUND: Pregnane X, encoded by the gene NR112, is a nuclear receptor whose primary role is to promote the detoxification and clearance of drugs and other foreign compounds from the body.AIM: The aim of this study was to analyze associations between NR1I2 polymorphisms, immunosuppressant drug exposure, and clinical outcomes in adult kidney transplant recipients.METHODS: Exposures to tacrolimus, mycophenolic acid, and total and free prednisolone were estimated at month 1 posttransplant using validated multiple regression-derived limited sampling strategies.RESULTS: In the 158 subjects studied, median (interquartile range) dose-adjusted exposure to tacrolimus was significantly higher in individuals carrying the NR1I2 8055T variant allele, when compared with exposure in wild-type individuals [20 (14, 22) μg·h/L/mg versus 15 (9, 24) μg·h/L/mg; P =0.0007]. Using multivariable logistic regression, NR1I2 8055T carrier status was independently predictive of higher dose-adjusted tacrolimus exposure (P=0.0005). Moreover, BK viremia was seen significantly more frequently in NR1I2 8055T allele carriers compared with wild-type individuals (38% vs 18%, P=0.005) and possession of the NR1I2 8055T allele imposed significantly higher odds of BK viremia (adjusted odds ratio, 2.76 [95% confidence interval, 1.33-7.73]; P=0.006). No significant difference in geometric mean peak BK viral replication titer was observed between 8055T carriers and noncarriers. No NR1I2 SNP or haplotype was significantly, independently associated with total or free prednisolone or MPA exposure.CONCLUSIONS: These data demonstrate an impact of pregnane X receptor polymorphisms on tacrolimus pharmacokinetics. Association of the 8055T allele with BK viremia suggests clinically significant "overimmunosuppression" in individuals with this genotype.

KW - Adult

KW - BK Virus

KW - Dose-Response Relationship, Drug

KW - Female

KW - Genotype

KW - Graft Rejection

KW - Haplotypes

KW - Humans

KW - Immunosuppressive Agents

KW - Incidence

KW - Kidney Transplantation

KW - Logistic Models

KW - Male

KW - Middle Aged

KW - Mycophenolic Acid

KW - Polymorphism, Single Nucleotide

KW - Prednisolone

KW - Prognosis

KW - Prospective Studies

KW - Receptors, Steroid

KW - Tacrolimus

KW - Viremia

U2 - 10.1097/TP.0b013e31826c3985

DO - 10.1097/TP.0b013e31826c3985

M3 - Journal article

VL - 94

SP - 1025

EP - 1032

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 10

ER -