Pharmacokinetic and Pharmacodynamic Interactions Between Henagliflozin, a Novel Selective SGLT-2 Inhibitor, and Warfarin in Healthy Chinese Subjects

Abstract

Purpose: While controlling blood glucose, patients with diabetes and abnormal coagulation should be treated with positive anticoagulation because the hypercoagulable state of their blood is the primary cause of macroangiopathy. The goal of this study was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD) interactions between henagliflozin, a novel selective sodium-glucose cotransporter 2 inhibitor, and warfarin in healthy subjects.

Methods: This single-center, open-label, single-arm clinical study was conducted in 16 healthy male Chinese subjects. According to the study protocol, the PK properties of henagliflozin 10 mg/d and warfarin 5 mg/d were collected and tabulated in accordance with sampling time. All study drugs were given with once-daily administration. Subjects were monitored for adverse reactions and their severity, outcomes, and relationship to study drug. This influences of warfarin on the PK properties of henagliflozin (C_max,ss and AUC_τ,ss), the effects of henagliflozin on the PK properties of warfarin (C_max, AUC_0-t, and AUC_0-∞), and the influences of henagliflozin on the PD properties of warfarin (PT_max, PT_AUC, INR_max, and INR_AUC) were evaluated.

Findings: The geometric mean ratios (GMRs; 90% CIs) of henagliflozin C_max,ss and AUC_τ,ss were 101.75% (96.11%-107.72%) and 102.21% (100.04%-104.42%), respectively. The GMRs (90% CIs) of S- and R-warfarin C_max, AUC_0-t, and AUC_0-∞ were as follows: C_max, 114.31% (106.30%-122.91%) and 115.09% (109.46%-121.01%), respectively; AUC_0-t, 120.15% (116.71%-123.69%) and 119.01% (116.32%-121.76%); and AUC_0-∞, 120.81% (117.17%-124.58%) and 121.94% (118.90%-125.05%). The GMRs (90% CIs) of warfarin PT_max and PT_AUC were 92.73% (91.25%-94.22%) and 97.42% (96.61%-98.24%). The GMRs (90% CIs) of warfarin INR_max and INR_AUC were 92.66% (91.17%-94.17%) and 97.36% (96.52%-98.21%). A total of 32 cases of mild adverse events were reported, and were recovered/resolved. There were no serious adverse events reported.

Implications: No significant clinically relevant effects on the PK/PD properties of henagliflozin or warfarin were found with coadministration of the two drugs in these healthy male Chinese subjects. Based on these findings, it is expected that henagliflozin and warfarin can be used in combination without dose adjustment. Chinadrugtrials.org.cn identifier: CTR20190240.

Keywords: Diabetes mellitus; Drug–drug interaction; Henagliflozin; SGLT-2 inhibitor; Warfarin.