Effect of linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers

Objective: To investigate the effect of the estimated highest therapeutic dose of linagliptin (5 mg) on the pharmacokinetics and pharmacodynamics of warfarin, a CYP2C9 substrate. Subjects and methods: This open-label, 2-period, fixed-sequence trial enrolled 18 healthy male volunteers, 17 of whom were homozygous for CYP2C9*1/*1. Subjects received a single oral dose of warfarin (10 mg) followed by a washout period of at least 14 days. Subjects then received oral linagliptin 5 mg once daily for 12 days (i.e. steady state) with a single dose of warfarin (10 mg) on Day 6. R(+) warfarin, S(-) warfarin, prothrombin time (PT) and international normalized ratio (INR) were assayed pre-dose and up to 168 h post-dose. Results: The geometric mean ratios (GMRs) (90% confidence interval (Cl)) of AUC(0-infinity), and C-max for (linagliptin + warfarin)/warfarin were 98.5 (95.7 - 101.5) and 99.7 (94.7 - 104.9), respectively, for R-warfarin; 103.0 (99.1 - 107.0) and 100.9 (93.7 - 108.6), respectively, for S-warfarin. Concomitant administration of linagliptin and warfarin had no clinically relevant effect on the AUC(0-168) for INR or PT. The GMRs (90% Cl) of INR and PT AUC(0-168) for (linagliptin + warfarin)/warfarin were 93.4 (86.2 - 101.1) and 103.2 (95.4 - 111.6), respectively. The corresponding E-max values for both INR and PT were slightly increased after co-administration of linagliptin and warfarin compared with warfarin alone, being 104.3 (85.2 - 127.6) and 115.1 (94.3 - 140.6), respectively, reflecting the higher variability of these endpoints. Co-administration of linagliptin and warfarin was well tolerated. Conclusions: Co-administration of linagliptin did not alter the pharmacokinetics or pharmacodynamics of R- or S-warfarin, indicating that no dosage adjustment for warfarin is necessary when co-administered with linagliptin.