Henagliflozein Proline

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.

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.

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.

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.

Sodium-glucose co-transporter type 2 (SGLT 2, gliflozins) inhibitors are potent orally active drugs approved for managing type 2 diabetes. SGLT 2 inhibitors exert a glucose-lowering effect by suppressing sodium-glucose co-transporters 1 and 2 in the intestinal and kidney proximal tubules. In this study, we developed a physiologically based pharmacokinetic (PBPK) model and simulated the concentrations of ertugliflozin, empagliflozin, henagliflozin, and sotagliflozin in target tissues. We used the perfusion-limited model to illustrate the disposition of SGLT 2 inhibitors in vivo. The modeling parameters were obtained from the references. Simulated steady-state plasma concentration-time curves of the ertugliflozin, empagliflozin, henagliflozin, and sotagliflozin are similar to the clinically observed curves. The 90% prediction interval of simulated excretion of drugs in urine captured the observed data well. Furthermore, all corresponding model-predicted pharmacokinetic parameters fell within a 2-fold prediction error. At the approved doses, we estimated the effective concentrations in intestinal and kidney proximal tubules and calculated the inhibition ratio of SGLT transporters to differentiate the relative inhibition capacities of SGLT1 and 2 in each gliflozin. According to simulation results, four SGLT 2 inhibitors can nearly completely inhibit SGLT 2 transporter at the approved dosages. Sotagliflozin exhibited the highest inhibition activity on SGLT1, followed by ertugliflozin, empagliflozin, and henagliflozin, which showed a lower SGLT 1 inhibitory effect. The PBPK model successfully simulates the specific target tissue concentration that cannot be measured directly and quantifies the relative contribution toward SGLT 1 and 2 for each gliflozin.