Effect of the GLP-1 agonist lixisenatide on the pharmacokinetics of warfarin

Results: GLP-1 agonists, e.g. lixisenatide (AVE0010), slow gastric emptying, which may alter the rate or extent of absorption of oral drugs. The effect of repeated daily doses of 20 μg lixisenatide on absorption of 25 mg warfarin was assessed in an open-label, single-center, randomized, 2-treatment, 2-sequence, cross-over study in 16 healthy male subjects. Subjects were randomized to one of two sequence groups to receive either sequence (A-B or B-A) of a single 25 mg oral warfarin dose given with breakfast on Day 1 (Treatment A) or lixisenatide given 30 min before breakfast plus concomitant 25 mg warfarin with breakfast on Day 11 (Treatment B). Lixisenatide-treated subjects received 10 μg SC injections for 7 days followed by 20 μg SC for an additional 10 days (i.e. warfarin was given on Day 4 of the 20 μg dose). Blood samples were taken at selected time points for up to 168 h on Day 1 (Treatment A) and Day 11 (Treatment B) to determine S- and R-warfarin concentrations in plasma. S-warfarin pharmacokinetic parameters are given in the table. There was no significant interaction of repeated dosing with lixisenatide 20 μg on the single-dose pharmacokinetics (AUClast, AUC) of 25 mg warfarin. Cmax of S-warfarin decreased when warfarin was given with lixisenatide vs. given alone; however, this was driven mainly by one subject only. Consistent with its effects on gastric emptying, lixisenatide increased tmax from a median of 1 h to 8 h. The pharmacodynamic effect of warfarin (using the INR) did not suggest any impact of concomitant lixisenatide treatment. Lixisenatide was well tolerated, with no serious or unexpected treatment-emergent effects. We conclude that there was no significant interaction of lixisenatide with warfarin on the overall drug exposure.