Effects Ofabcb1,Ugt1a1, Andugt1a9genetic Polymorphisms On The Pharmacokinetics Of Sitafloxacin Granules In Healthy Subjects

Sitafloxacin, a new fluoroquinolone, has strong antibacterial activity. We evaluated the effects of sitafloxacin granules in single-dose and multidose cohorts and the effects ofABCB1, UGT1A1, andUGT1A9genetic polymorphisms on the pharmacokinetics (PK) of sitafloxacin in healthy subjects. The single-dose study included 3 fasted cohorts receiving 50, 100, and 200 mg of sitafloxacin granules and 1 cohort receiving 50 mg of sitafloxacin granules with a high-fat meal. The multidose study included 1 cohort receiving 100 mg of sitafloxacin granules once daily for 5 days. PK parameters were calculated using noncompartmental parameters based on concentration-time data. The genotypes forABCB1,UGT1A1, andUGT1A9single-nucleotide polymorphisms were determined using Sanger sequencing. Subsequently, the association between sitafloxacin PK parameters and target single-nucleotide polymorphisms was analyzed. Sitafloxacin granules were well tolerated up to 200 and 100 mg in the single-dose and multidose studies, respectively. Sitafloxacin AUC and C(max)increased linearly within the detection range, and a steady state was reached within 3 days after the administration of multiple oral doses. Our findings showed that C(max)was lower in theABCB1(rs1045642) mutation group, whereas t(1/2)was longer in theUGT1A1(rs2741049) andUGT1A9(rs3832043) mutation groups. In conclusion, sitafloxacin granules were safe at single doses and multiple doses up to 200 and 100 mg/day, respectively, with a linear plasma PK profile. However,ABCB1(rs1045642),UGT1A1(rs2741049), andUGT1A9(rs3832043) genetic polymorphisms are likely to influence the C(max)or t(1/2)and thereby merit further clinical evaluation.