Evaluation of a potential tigecycline-warfarin drug interaction

Abstract

Study objective: To evaluate the potential for a clinically significant drug interaction between tigecycline and warfarin by using pharmacokinetic and anticoagulant assessments.

Design: Open-label, nonrandomized study.

Setting: Inpatient clinical pharmacology unit.

Subjects: Nineteen healthy male volunteers were enrolled; eight completed all study assessments.

Intervention: All subjects received a single oral dose of warfarin 25 mg (day 1). Seven days later (day 8), they received a 100-mg loading dose of intravenous tigecycline, followed by 50 mg every 12 hours for eight additional doses. On day 12, they received another single oral dose of warfarin 25-mg with their last dose of tigecycline.

Measurements and main results: Serum tigecycline and plasma R- and S-warfarin concentrations were determined by high-performance liquid chromatography with tandem mass spectroscopy. Pharmacokinetic parameters were calculated by using noncompartmental methods and analyzed by the two 1-sided tests equivalence procedure. Pharmacodynamic analyses were based on anticoagulant parameters derived from international normalized ratios of prothrombin times. Tigecycline peak concentration, trough concentration, area under the concentration-time curve (AUC) from 0-12 hrs, and clearance were not affected by single-dose warfarin. In contrast, R- and S-warfarin AUC from time zero extrapolated to infinity was increased by 68% and 29%, respectively, and clearance was decreased by 40% and 23%, respectively, when warfarin was administered after eight doses of tigecycline. Nevertheless, tigecycline did not alter the anticoagulant effects of warfarin, which is consistent with a mechanism based only on increased warfarin protein binding.

Conclusion: These results suggest that a dosage adjustment of either drug is not necessary during coadministration of tigecycline and warfarin. However, consistent with good medical practice, the anticoagulant activity of warfarin should be monitored during coadministration with tigecycline.