Screening study for genetic polymorphisms affecting pharmacokinetics of talniflumate

ABSTRACT

Talniflumate is a phthalidyl ester of niflumic acid, which has potent analgesic and anti-inflammatory effects and is widely used to treat inflammatory disorders, such as rheumatoid arthritis. To screen the possible genetic factors affecting the pharmacokinetics (PK) of talniflumate, 23 male Korean volunteers were enrolled from two separate bioequivalence studies. All subjects received 740 mg (two tablets) talniflumate in a standard 2×2 cross-over model in a randomized order. For the genetic study, PK parameters of the reference drug were used. We used Illumina Human610Quad v1.0 DNA Analysis BeadChip for whole genome single nucleotide polymorphism (SNP) analysis and whole genome genotyping data were processed by linear regression analysis for PK parameters. Whole genome analysis revealed 1498 significant SNPs (P < 0.0001) for Cmax, 65 significant SNPs (P < 0.0001) for T(max), and 1491 significant SNPs (P < 0.0001) for AUC(inf). For clinical pharmacological purposes, we selected SNPs from drug metabolizing enzymes and transporters, and analyzed the PK parameters of various genotypes. Two SNPs (rs11165069 from ABCA4 (p=0.00002); rs17847036 from CYP2C9 (p=0.000001)) showed significant associations with talniflumate C(max). In the T(max) group, two SNPs (rs3787555 from CYP24A1 (p=0.00035); rs2275034 from ABCA4 (p=0.000587)) showed significant associations with talniflumate T(max). In the AUC(inf) group, two SNPs (rs11165069 from ABCA4 (p=0.00002); rs12461006 from SLC1A6 (p=0.00008)) exhibited significant associations with talniflumate absorption. These results show that genetic factors could affect the PK parameters, and provide information that may be used in the development of personalized talniflumate therapy.