title: 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.
authors.affiliation: Translational Medicine & Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Vandell
authors.affiliation: Translational Medicine & Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: Translational Medicine & Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: M
authors.initials: M
authors.lastname: Shi
authors.affiliation: Pharsight Consulting Services, Montreal, Quebec, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Rubets
authors.affiliation: Translational Medicine & Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Brown
authors.affiliation: Translational Medicine & Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Walker
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000483:Alleles; D005260:Female; D005838:Genotype; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics*; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics; D000071185:Pharmacogenomic Testing / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011725:Pyridines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011725:Pyridines; C503999:SLCO1B1 protein, human; D013844:Thiazoles; C552171:edoxaban