An integrated pharmacokinetic/pharmacogenomic analysis of ABCB1 and SLCO1B1 polymorphisms on edoxaban exposure

Abstract

Edoxaban and its low-abundance, active metabolite M4 are substrates of P-glycoprotein (P-gp; MDR1) and organic anion transporter protein 1B1 (OATP1B1), respectively, and pharmacological inhibitors of P-gp and OATP1B1 can affect edoxaban and M4 pharmacokinetics (PK). In this integrated pharmacogenomic analysis, genotype and concentration–time data from 458 healthy volunteers in 14 completed phase 1 studies were pooled to examine the impact on edoxaban PK parameters of allelic variants of ABCB1 (rs1045642: C3435T) and SLCO1B1 (rs4149056: T521C), which encode for P-gp and OATP1B1. Although some pharmacologic inhibitors of P-gp and OATP1B1 increase edoxaban exposure, neither the ABCB1 C3435T nor the SLCO1B1 T521C polymorphism affected edoxaban PK. A slight elevation in M4 exposure was observed among SLCO1B1 C-allele carriers; however, this elevation is unlikely to be clinically significant as plasma M4 concentrations comprise <10% of total edoxaban levels.

Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation

“…For dabigatran, a direct thrombin inhibitor, an SNP of carboxyesterase 1, which rapidly hydrolyses the prodrug (dabigatran etexilate) to dabigatran, is related to low trough concentrations of dabigatran and the risk of bleeding . For both rivaroxaban and edoxaban, which are FXa inhibitors, no ABCB1 polymorphisms affect these pharmacokinetics . However, our previous pharmacogenomic study indicated that trough concentrations of apixaban are associated with the ABCG2 421A/A and CYP3A5 *3 genotypes .…”

“…The clinical effectiveness of anticoagulants has been examined in relation to drug transporter and metabolizing enzyme single nucleotide polymorphisms (SNPs) [18][19][20][21][22][23]. Recent studies suggested that precision medicine using vitamin K epoxide reductase complex 1 (VKORC1) and CYP2C9 genotypes is clinically useful for pharmacotherapy of warfarin [18][19][20].…”

Influence of <em>ABCB1</em> and <em>CYP3A5</em> gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke

“…Nowadays, there is a growing body of literature showing significance of genetic characteristics of patients with respect to metabolism and the distribution of NOACs. 7 – 9 …”

Pharmacogenetic Aspects of New Oral Anticoagulants Application

“…В исследовании Vandell и др. [7] изучалось влияние на фармакокинетику эдоксабана аллельного вариан-та гена ABCB1 rs1045642, который кодирует Р-гликопротеин. В анализ были включены 458 здоровых добровольцев, принимавших участие в 14 исследованиях I фазы.…”

“…В работе Vandell и др. [7] также исследовалось влияние полиморфизма rs4149056 гена SLCO1B1 на фармакокинетику эдоксабана. По данному аллельному варианту 384 добровольца имели генотип ТТ, 71 доброволец -генотип СТ, 3 добровольца -генотип СС.…”