Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms

Towards addressing the missing heritability in pharmacogenetic phenotypes?

Janine E. Micheli, Leslie W. Chinn, Sarah B. Shugarts, Ashish Patel, Jeffrey N. Martin, David Bangsberg, Deanna L. Kroetz

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

OBJECTIVE: Nevirapine is an important component of highly active antiretroviral therapy used in the treatment of HIV infection. There is a considerable variation in the pharmacokinetics of nevirapine and this variation can impact the efficacy and toxicity of nevirapine. Although some of this variation can be attributed to environmental factors, the degree to which heritability influences nevirapine pharmacokinetics is unknown. This study aims to estimate how much variation in nevirapine pharmacokinetics is due to genetic factors and to investigate the contribution of selected polymorphisms to this variability. METHODS: Two doses of immediate-release nevirapine were administered to European (n=11) and African American (n=6) participants recruited from the Research in Access to Care in the Homeless cohort. A repeated drug administration method was then used to determine the relative genetic contribution (rGC) to variability in nevirapine AUC0-6 h. Nevirapine plasma levels were quantified using LC/MS/MS. Patients were also genotyped for selected polymorphisms in candidate genes that may influence nevirapine pharmacokinetics. RESULTS: A significant rGC for nevirapine AUC0-6 h was found in Europeans (P=0.02) and African Americans (P=0.01). A trend toward higher nevirapine AUC0-6 h for the CYP2B6 516TT (rs3745274; Q172H) genotype was observed in European Americans (P=0.19). CONCLUSION: This study demonstrates that there is a significant genetic component to variability in nevirapine pharmacokinetics. Although genetic variants such as CYP2B6 polymorphisms attributed to some of this variation, these data suggest that there may be additional genetic factors that influence nevirapine pharmacokinetics.

Original languageEnglish (US)
Pages (from-to)591-596
Number of pages6
JournalPharmacogenetics and Genomics
Volume23
Issue number11
DOIs
StatePublished - Nov 2013
Externally publishedYes

Fingerprint

Nevirapine
Pharmacogenetics
Pharmacokinetics
Phenotype
African Americans
Highly Active Antiretroviral Therapy
HIV Infections

Keywords

  • CYP2B6
  • Human immunodeficiency virus
  • Nevirapine
  • Pharmacogenetics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms : Towards addressing the missing heritability in pharmacogenetic phenotypes? / Micheli, Janine E.; Chinn, Leslie W.; Shugarts, Sarah B.; Patel, Ashish; Martin, Jeffrey N.; Bangsberg, David; Kroetz, Deanna L.

In: Pharmacogenetics and Genomics, Vol. 23, No. 11, 11.2013, p. 591-596.

Research output: Contribution to journalArticle

Micheli, Janine E. ; Chinn, Leslie W. ; Shugarts, Sarah B. ; Patel, Ashish ; Martin, Jeffrey N. ; Bangsberg, David ; Kroetz, Deanna L. / Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms : Towards addressing the missing heritability in pharmacogenetic phenotypes?. In: Pharmacogenetics and Genomics. 2013 ; Vol. 23, No. 11. pp. 591-596.
@article{6ca00b78251949fe86e902168f29a6a4,
title = "Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms: Towards addressing the missing heritability in pharmacogenetic phenotypes?",
abstract = "OBJECTIVE: Nevirapine is an important component of highly active antiretroviral therapy used in the treatment of HIV infection. There is a considerable variation in the pharmacokinetics of nevirapine and this variation can impact the efficacy and toxicity of nevirapine. Although some of this variation can be attributed to environmental factors, the degree to which heritability influences nevirapine pharmacokinetics is unknown. This study aims to estimate how much variation in nevirapine pharmacokinetics is due to genetic factors and to investigate the contribution of selected polymorphisms to this variability. METHODS: Two doses of immediate-release nevirapine were administered to European (n=11) and African American (n=6) participants recruited from the Research in Access to Care in the Homeless cohort. A repeated drug administration method was then used to determine the relative genetic contribution (rGC) to variability in nevirapine AUC0-6 h. Nevirapine plasma levels were quantified using LC/MS/MS. Patients were also genotyped for selected polymorphisms in candidate genes that may influence nevirapine pharmacokinetics. RESULTS: A significant rGC for nevirapine AUC0-6 h was found in Europeans (P=0.02) and African Americans (P=0.01). A trend toward higher nevirapine AUC0-6 h for the CYP2B6 516TT (rs3745274; Q172H) genotype was observed in European Americans (P=0.19). CONCLUSION: This study demonstrates that there is a significant genetic component to variability in nevirapine pharmacokinetics. Although genetic variants such as CYP2B6 polymorphisms attributed to some of this variation, these data suggest that there may be additional genetic factors that influence nevirapine pharmacokinetics.",
keywords = "CYP2B6, Human immunodeficiency virus, Nevirapine, Pharmacogenetics, Pharmacokinetics",
author = "Micheli, {Janine E.} and Chinn, {Leslie W.} and Shugarts, {Sarah B.} and Ashish Patel and Martin, {Jeffrey N.} and David Bangsberg and Kroetz, {Deanna L.}",
year = "2013",
month = "11",
doi = "10.1097/FPC.0b013e32836533a5",
language = "English (US)",
volume = "23",
pages = "591--596",
journal = "Pharmacogenetics and Genomics",
issn = "1744-6872",
publisher = "Lippincott Williams and Wilkins",
number = "11",

}

TY - JOUR

T1 - Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms

T2 - Towards addressing the missing heritability in pharmacogenetic phenotypes?

AU - Micheli, Janine E.

AU - Chinn, Leslie W.

AU - Shugarts, Sarah B.

AU - Patel, Ashish

AU - Martin, Jeffrey N.

AU - Bangsberg, David

AU - Kroetz, Deanna L.

PY - 2013/11

Y1 - 2013/11

N2 - OBJECTIVE: Nevirapine is an important component of highly active antiretroviral therapy used in the treatment of HIV infection. There is a considerable variation in the pharmacokinetics of nevirapine and this variation can impact the efficacy and toxicity of nevirapine. Although some of this variation can be attributed to environmental factors, the degree to which heritability influences nevirapine pharmacokinetics is unknown. This study aims to estimate how much variation in nevirapine pharmacokinetics is due to genetic factors and to investigate the contribution of selected polymorphisms to this variability. METHODS: Two doses of immediate-release nevirapine were administered to European (n=11) and African American (n=6) participants recruited from the Research in Access to Care in the Homeless cohort. A repeated drug administration method was then used to determine the relative genetic contribution (rGC) to variability in nevirapine AUC0-6 h. Nevirapine plasma levels were quantified using LC/MS/MS. Patients were also genotyped for selected polymorphisms in candidate genes that may influence nevirapine pharmacokinetics. RESULTS: A significant rGC for nevirapine AUC0-6 h was found in Europeans (P=0.02) and African Americans (P=0.01). A trend toward higher nevirapine AUC0-6 h for the CYP2B6 516TT (rs3745274; Q172H) genotype was observed in European Americans (P=0.19). CONCLUSION: This study demonstrates that there is a significant genetic component to variability in nevirapine pharmacokinetics. Although genetic variants such as CYP2B6 polymorphisms attributed to some of this variation, these data suggest that there may be additional genetic factors that influence nevirapine pharmacokinetics.

AB - OBJECTIVE: Nevirapine is an important component of highly active antiretroviral therapy used in the treatment of HIV infection. There is a considerable variation in the pharmacokinetics of nevirapine and this variation can impact the efficacy and toxicity of nevirapine. Although some of this variation can be attributed to environmental factors, the degree to which heritability influences nevirapine pharmacokinetics is unknown. This study aims to estimate how much variation in nevirapine pharmacokinetics is due to genetic factors and to investigate the contribution of selected polymorphisms to this variability. METHODS: Two doses of immediate-release nevirapine were administered to European (n=11) and African American (n=6) participants recruited from the Research in Access to Care in the Homeless cohort. A repeated drug administration method was then used to determine the relative genetic contribution (rGC) to variability in nevirapine AUC0-6 h. Nevirapine plasma levels were quantified using LC/MS/MS. Patients were also genotyped for selected polymorphisms in candidate genes that may influence nevirapine pharmacokinetics. RESULTS: A significant rGC for nevirapine AUC0-6 h was found in Europeans (P=0.02) and African Americans (P=0.01). A trend toward higher nevirapine AUC0-6 h for the CYP2B6 516TT (rs3745274; Q172H) genotype was observed in European Americans (P=0.19). CONCLUSION: This study demonstrates that there is a significant genetic component to variability in nevirapine pharmacokinetics. Although genetic variants such as CYP2B6 polymorphisms attributed to some of this variation, these data suggest that there may be additional genetic factors that influence nevirapine pharmacokinetics.

KW - CYP2B6

KW - Human immunodeficiency virus

KW - Nevirapine

KW - Pharmacogenetics

KW - Pharmacokinetics

UR - http://www.scopus.com/inward/record.url?scp=84886583431&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84886583431&partnerID=8YFLogxK

U2 - 10.1097/FPC.0b013e32836533a5

DO - 10.1097/FPC.0b013e32836533a5

M3 - Article

VL - 23

SP - 591

EP - 596

JO - Pharmacogenetics and Genomics

JF - Pharmacogenetics and Genomics

SN - 1744-6872

IS - 11

ER -