Pharmacogenomics of novel direct oral anticoagulants: Newly identified genes and genetic variants

Sri H. Kanuri, Rolf Kreutz

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.

Original languageEnglish (US)
JournalJournal of Personalized Medicine
Volume9
Issue number1
DOIs
StatePublished - Mar 1 2019

Fingerprint

Pharmacogenetics
Anticoagulants
Drug Interactions
Pharmaceutical Preparations
Genes
Single Nucleotide Polymorphism
Glycoproteins
Pharmacokinetics
Factor Xa
Genetic Loci
Research
PubMed
Clinical Trials
DNA
Dabigatran
Rivaroxaban
apixaban
edoxaban

Keywords

  • Apixaban
  • Dabigatran
  • Direct oral anticoagulant
  • Edoxaban
  • Gene-drug interactions
  • Genetic variants
  • Genome guided therapy
  • Pharmacogenomics
  • Rivaroxaban
  • SNPs

ASJC Scopus subject areas

  • Medicine (miscellaneous)

Cite this

Pharmacogenomics of novel direct oral anticoagulants : Newly identified genes and genetic variants. / Kanuri, Sri H.; Kreutz, Rolf.

In: Journal of Personalized Medicine, Vol. 9, No. 1, 01.03.2019.

Research output: Contribution to journalArticle

@article{50e077911feb4164a94341fd1046a299,
title = "Pharmacogenomics of novel direct oral anticoagulants: Newly identified genes and genetic variants",
abstract = "Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.",
keywords = "Apixaban, Dabigatran, Direct oral anticoagulant, Edoxaban, Gene-drug interactions, Genetic variants, Genome guided therapy, Pharmacogenomics, Rivaroxaban, SNPs",
author = "Kanuri, {Sri H.} and Rolf Kreutz",
year = "2019",
month = "3",
day = "1",
doi = "10.3390/jpm9010007",
language = "English (US)",
volume = "9",
journal = "Journal of Personalized Medicine",
issn = "2075-4426",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "1",

}

TY - JOUR

T1 - Pharmacogenomics of novel direct oral anticoagulants

T2 - Newly identified genes and genetic variants

AU - Kanuri, Sri H.

AU - Kreutz, Rolf

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.

AB - Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.

KW - Apixaban

KW - Dabigatran

KW - Direct oral anticoagulant

KW - Edoxaban

KW - Gene-drug interactions

KW - Genetic variants

KW - Genome guided therapy

KW - Pharmacogenomics

KW - Rivaroxaban

KW - SNPs

UR - http://www.scopus.com/inward/record.url?scp=85063163548&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063163548&partnerID=8YFLogxK

U2 - 10.3390/jpm9010007

DO - 10.3390/jpm9010007

M3 - Article

AN - SCOPUS:85063163548

VL - 9

JO - Journal of Personalized Medicine

JF - Journal of Personalized Medicine

SN - 2075-4426

IS - 1

ER -