No apparent pharmacokinetic interactions were found between henagliflozin: A novel sodium-glucose co-transporter 2 inhibitor and glimepiride in healthy Chinese male subjects.

WHAT IS KNOWN AND OBJECTIVE: Henagliflozin is a novel selective sodium-glucose co-transporter 2 (SGLT2) inhibitor with similar inhibitory effect to ertugliflozin. Glimepiride is widely used to treat type 2 diabetes mellitus (T2DM) with few cardiovascular side effects. In the present study, we aimed at evaluating the pharmacokinetic (PK) interactions between henagliflozin and glimepiride. METHODS: An open-label, single-centre, single-arm, 3-period, 3-treatment, self-control study was conducted in twelve healthy Chinese male subjects. During each study period, subjects received a single oral dose of glimepiride 2 mg, multiple oral doses of henagliflozin 10 mg or a combination of the two drugs. Serial blood samples were collected 24 h post-dosing for PK analyses. Finger-tip blood glucose was also tested for safety evaluation. RESULTS AND DISCUSSION: Co-administration of henagliflozin with glimepiride did not affect their plasma PK profiles. For henagliflozin, the 90% confidence intervals for the geometric mean ratio (GMR) for the maximum plasma concentrations at steady-state (Cmax ss ) and the area under the plasma concentration-time curve during a dosing interval at steady-state (AUCτ, ss ) of combination therapy to henagliflozin alone were 1.00 (0.93-1.08) and 1.00 (0.98-1.02), respectively. For glimepiride, the corresponding values of combination therapy to glimepiride alone were 1.00 (0.88-1.13) for maximum plasma concentrations (Cmax ), 0.91 (0.84-0.99) for the area under the plasma concentration-time curve from 0-24 h (AUC0-24h ) and 0.91 (0.83-1.00) for the plasma concentration-time curve from 0 h to infinite (AUC0-inf ), respectively. All values fell within the equivalence range of 0.8-1.25. All monotherapies and combination therapy led to no serious adverse events and were well tolerated. WHAT IS NEW AND CONCLUSION: Multiple doses of henagliflozin did not exert a significant change on glimepiride PK profiles and a single dose of glimepiride had little effect on henagliflozin blood concentration. Thus, henagliflozin can be co-administered with glimepiride without dose adjustment of either drug.

Henagliflozin monotherapy in patients with type 2 diabetes inadequately controlled on diet and exercise: A randomized, double-blind, placebo-controlled, phase 3 trial.

AIM: To evaluate henagliflozin, a novel sodium-glucose co-transporter-2 inhibitor, as monotherapy in patients with type 2 diabetes and inadequate glycaemic control with diet and exercise. MATERIALS AND METHODS: This multicentre trial included a 24-week, randomized, double-blind, placebo-controlled period, followed by a 28-week extension period. Four hundred and sixty-eight patients with an HbA1c of 7.0%-10.5% were randomly assigned (1:1:1) to receive once-daily placebo, or 5 or 10 mg henagliflozin. After 24 weeks, patients on placebo were switched to 5 or 10 mg henagliflozin, and patients on henagliflozin maintained the initial therapy. The primary endpoint was the change in HbA1c from baseline after 24 weeks. RESULTS: At Week 24, the placebo-adjusted least squares (LS) mean changes from baseline in HbA1c were -0.91% (95% CI: -1.11% to -0.72%; P < .001) and -0.94% (-1.13% to -0.75%; P < .001) with henagliflozin 5 and 10 mg, respectively; the placebo-adjusted LS mean changes were -1.3 (-1.8 to -0.9) and -1.5 (-2.0 to -1.1) kg in body weight, and -5.1 (-7.2 to -3.0) and -4.4 (-6.5 to -2.3) mmHg in systolic blood pressure (all P < .05). The trends of these improvements were sustained for an additional 28 weeks. Adverse events occurred in 81.0%, 78.9% and 78.9% of patients in the placebo, henagliflozin 5 and 10 mg groups, respectively. No diabetic ketoacidosis or major episodes of hypoglycaemia occurred. CONCLUSIONS: Henagliflozin 5 mg and 10 mg as monotherapy provided effective glycaemic control, reduced body weight and blood pressure, and was generally well tolerated.

Henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, placebo-controlled, phase 3 trial.

AIM: To evaluate the efficacy and safety of henagliflozin in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin. MATERIAL AND METHODS: This multicentre phase 3 trial included a 24-week randomized, double-blind, placebo-controlled period, followed by a 28-week extension period. Patients with a glycated haemoglobin (HbA1c) level of 7.0% (53 mmol/mol) to 10.5% (91 mmol/mol) were randomized and treated with once-daily placebo (n = 161), henagliflozin 5 mg (n = 162), or henagliflozin 10 mg (n = 160). After 24 weeks, patients on placebo were switched to 5 mg or 10 mg henagliflozin for the additional 28-week treatment, and patients on henagliflozin during 24-week treatment period maintained this initial therapy. The primary endpoint was change in HbA1c from baseline to Week 24. RESULTS: At Week 24, the least squares mean HbA1c changes versus placebo from baseline were - 0.76% (-8.3 mmol/mol) and - 0.80% (-8.7 mmol/mol) for henagliflozin 5 and 10 mg, respectively (all P < 0.0001). Compared with the placebo group, both doses of henagliflozin lowered fasting plasma glucose, 2-hour postprandial plasma glucose, body weight and blood pressure, and increased the proportions of patients achieving HbA1c <7.0% (53 mmol/mol) at Week 24. The trends in these improvements were sustained over an additional 28 weeks. Slightly higher proportions of ketosis and presence of urine ketone bodies were observed in patients treated with henagliflozin compared to placebo at Week 24. No diabetic ketoacidosis or episodes of severe hypoglycaemia were reported. CONCLUSIONS: Henagliflozin 5 mg or 10 mg as add-on therapy to metformin provided a new therapeutic option for the treatment of T2DM patients who have inadequate glycaemic control with metformin alone, and was generally well tolerated.

Evaluation of drug-drug interaction between henagliflozin, a novel sodium-glucose co-transporter 2 inhibitor, and metformin in healthy Chinese males.

1. Henagliflozin is a novel sodium-glucose transporter 2 inhibitor and presents a complementary therapy to metformin for patients with T2DM due to its insulin-independent mechanism of action. This study evaluated the potential pharmacokinetic drug-drug interaction between henagliflozin and metformin in healthy Chinese male subjects. 2. In open-label, single-center, single-arm, two-period, three-treatment self-control study, 12 subjects received 25 mg henagliflozin, 1000 mg metformin or the combination. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination: monotherapy being within the range of 0.80-1.25. 3. Co-administration of henagliflozin with metformin had no effect on henagliflozin area under the plasma concentration-time curve (AUC0-24) (GRM: 1.08; CI: 1.05, 1.10) and peak plasma concentration (Cmax) (GRM: 0.99; CI: 0.92, 1.07). Reciprocally, co-administration of metformin with henagliflozin had no clinically significant on metformin AUC0-24 (GRM: 1.09, CI: 1.02, 1.16) although there was an 11% increase in metformin Cmax (GRM 1.12; CI 1.02, 1.23). All monotherapies and combination therapy were well tolerated. 4. Henagliflozin can be co-administered with metformin without dose adjustment of either drug.

Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Proline Henagliflozin in Chinese Subjects with Varying Degrees of Liver Dysfunction.

Proline henagliflozin, a novel selective inhibitor of sodium glucose cotransporter 2, is a treatment for type 2 diabetes mellitus. We designed a parallel-group, open-label, and multicenter study to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety profiles of henagliflozin in Chinese subjects with varying degrees of liver dysfunction. Thirty-two subjects were enrolled and divided into four groups based on liver function (normal liver function, mild, moderate, or severe liver dysfunction). The area under the plasma concentration from time zero to infinity of henagliflozin in subjects with mild liver dysfunction, moderate liver dysfunction, and severe liver dysfunction compared with normal liver function was increased by 137%, 197%, and 204%, respectively. The maximum plasma concentration was also increased by 123%, 129%, and 139%, respectively. PK parameters of three metabolites varied to different degrees in the liver dysfunction groups than in the normal liver function group. The mean accumulative excretion amounts and fraction of dose excreted in urine expressed as a percentage were all increased with the decrease of liver function. The PD parameters were significantly higher in liver dysfunction groups than those in the normal liver function group. However, the urine creatinine (UCr) was not significantly different among the groups. No notable adverse events or adverse drug reactions were observed. Due to the higher exposures in subjects with liver dysfunction, the benefit: risk ratio should be individually assessed because the long-term safety profile and efficacy have not been specifically studied in this population.

Evaluation of Drug-Drug Interaction Between Henagliflozin and Hydrochlorothiazide in Healthy Chinese Volunteers.

Purpose: Henagliflozin is an original, selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. Hydrochlorothiazide (HCTZ) is a common anti-hypertensive drug. This study aimed to evaluate the potential interaction between henagliflozin and HCTZ. Methods: This was a single-arm, open-label, multi-dose, three-period study that was conducted in healthy Chinese volunteers. Twelve subjects were treated in three periods, period 1: 25 mg HCTZ for four days, period 2: 10 mg henagliflozin for four days and period 3: 25 mg HCTZ + 10 mg henagliflozin for four days. Blood samples and urine samples were collected before and up to 24 hours after drug administrations on day 4, day 10 and day 14. The plasma concentrations of henagliflozin and HCTZ were analyzed using LC-MS/MS. The urine samples were collected for pharmacodynamic glucose and electrolyte analyses. Tolerability was also evaluated. Results: The 90% CI of the ratio of geometric means (combination: monotherapy) for AUCτ,ss of henagliflozin and HCTZ was within the bioequivalence interval of 0.80-1.25. For henagliflozin, co-administration increased Css, max by 24.32% and the 90% CI of the GMR was (108.34%, 142.65%), and the 24-hour urine volume and glucose excretion decreased by 0.43% and 19.6%, respectively. For HCTZ, co-administration decreased Css, max by 19.41% and the 90% CI of the GMR was (71.60%, 90.72%), and the 24-hour urine volume and urinary calcium, potassium, phosphorus, chloride, and sodium excretion decreased by 11.7%, 20.8%, 11.8%, 11.9%, 22.0% and 15.5%, respectively. All subjects (12/12) reported adverse events (AEs), but the majority of theses AEs were mild and no serious AEs were reported. Conclusion: Although Css,max was affected by the combination of henagliflozin and HCTZ, there was no clinically meaningful safety interaction between them. Given these results, coadministration of HCTZ should not require any adaptation of henagliflozin dosing. Trial Registration: ClinicalTrials.gov NCT06083116.

Effects of Food and Multiple-dose Administration on the Pharmacokinetic Properties of HR20033, a Sustained-release Formulation of Henagliflozin and Metformin for the Treatment of Diabetes, in Healthy Chinese Volunteers.

Henagliflozin proline and metformin hydrochloride sustained-release tablets (HR20033) are a fixed-dose combination of the novel, highly selective, and effective sodium-glucose cotransporter-2 inhibitor henagliflozin, with a metformin sustained-release layer for the treatment of type 2 diabetes mellitus in conjunction with dietary control and exercise. The aims of this study were to investigate the effect of a high-fat diet on the pharmacokinetics of henagliflozin and metformin after a single administration of HR20033 and the effect of repeated oral administration of HR20033 on their pharmacokinetics in healthy volunteers. The food-effect clinical study involved 18 healthy subjects randomized to receive either HR20033 in the fasted condition followed by HR20033 in the fed condition or the reverse schedule, with the two doses separated by a washout period of at least 7 days. The multiple-dose clinical study was conducted on 10 healthy subjects. In the food-effect study, compared with those in the fasted condition, the area under the blood concentration curve (AUC) and peak concentration (Cmax ) of henagliflozin decreased by 12.64% and 40.89%, respectively, while the AUC of metformin increased by 31.13% and Cmax decreased by 7.09% in the fed state. There was no significant accumulation of HR20033 in the body after multiple oral doses. No serious adverse event was observed in either of the two clinical studies. Food did not have a clinically meaningful effect on the absorption of HR20033.

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

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 (Cmax,ss and AUCτ,ss), the effects of henagliflozin on the PK properties of warfarin (Cmax, AUC0-t, and AUC0-∞), and the influences of henagliflozin on the PD properties of warfarin (PTmax, PTAUC, INRmax, and INRAUC) were evaluated. FINDINGS: The geometric mean ratios (GMRs; 90% CIs) of henagliflozin Cmax,ss and AUCτ,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 Cmax, AUC0-t, and AUC0-∞ were as follows: Cmax, 114.31% (106.30%-122.91%) and 115.09% (109.46%-121.01%), respectively; AUC0-t, 120.15% (116.71%-123.69%) and 119.01% (116.32%-121.76%); and AUC0-∞, 120.81% (117.17%-124.58%) and 121.94% (118.90%-125.05%). The GMRs (90% CIs) of warfarin PTmax and PTAUC were 92.73% (91.25%-94.22%) and 97.42% (96.61%-98.24%). The GMRs (90% CIs) of warfarin INRmax and INRAUC 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.

Characterization and quantitative determination of henagliflozin metabolites in humans.

Henagliflozin is a highly specific inhibitor of sodium-glucose co-transporter-2 (SGLT2) proposed as a more efficient medication for type 2 diabetes mellitus (T2DM). In this work, henagliflozin metabolic profile was investigated in human plasma and urine samples using a newly developed high-performance liquid chromatography coupled with time-of-flight mass spectrometry (HPLC/Q-TOF MS) method. A total of 8 metabolites were observed, while the structures of four major metabolites, including M1 (O-deethylation metabolite), M5-1 (2-O-ß-glucuronide conjugate), M5-2 (6-O-ß-glucuronide conjugate), and M5-3 (3-O-ß-glucuronide conjugate) were confirmed in our study after comparison with the reference standards. The principal henagliflozin metabolic pathways were identified as glucuronidation and O-deethylation in humans. The principal form of henagliflozin in human plasma was parent drug, followed by M5-1; while it was M5-3 and M5-1 in urine. Subsequently, an accurate and simple LC-MS/MS method was developed for simultaneously determine M5-1, M5-2, and M5-3 in human plasma. After optimization of this method, three M5 isomers were successfully separated and quantified using chromatography. Acetonitrile-induced protein precipitation method was adapted for extracting the analytes from human plasma. Separation was conducted using Gemini C18 column under gradient elution with 5 mM aqueous ammonium acetate (A) and acetonitrile (B) mobile phases. Negative electrospray ionization was conducted using a selective reaction monitoring with the same transition of m/z 629→321 for detection of three M5 isomers. The method showed good linearities for M5-1, M5-2, and M5-3 within the range of 1.00-150 ng/mL, 0.500-75.0 ng/mL, and 1.00-150 ng/mL, respectively. Conclusively, the method has been applied successfully to assess phase I henagliflozin pharmacokinetics and pharmacodynamics and providing effective safety evaluations.

Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Henagliflozin, a Novel Selective Inhibitor of Sodium-Glucose Cotransporter 2, in Healthy Subjects Following Single- and Multiple-dose Administration.

BACKGROUND: Henagliflozin, a novel selective inhibitor of sodium-glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus. PURPOSE: To evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers. METHODS: Two clinical studies were conducted. One was a single ascending dose (SAD) study (2.5-200 mg) involving 80 healthy subjects, and the other was a multiple ascending dose (MAD) study (1.25-100 mg for 10 days) involving 48 healthy subjects. The tolerability, PK profiles of henagliflozin and its main metabolites, and the urinary glucose excretion over 24 h were characterized in these 2 studies. FINDINGS: No serious adverse events were observed in the healthy subjects after single- and multiple-dose oral administration of henagliflozin, suggesting that this drug was well tolerated. Henagliflozin was rapidly absorbed, with a Tmax of 1.5-3 h, and then eliminated from plasma with a half-life of 11-15 h. It was not accumulated following once-daily oral administration. Plasma exposure of henagliflozin exhibited dose-proportional PK properties over the dose ranges of 2.5-200 mg (SAD) and 1.25-100 mg (MAD). The excretion of henagliflozin in urine was found to be very low, with 3.00%-5.13% of the dose. The glucuronide metabolites M5-1, M5-2 and M5-3 were the main metabolites detected in plasma samples, which accounted for up to 54.3%, 19.8%, and 27.5%, respectively, of the parent drug at steady state. Both the SAD and MAD studies demonstrated that the urinary glucose excretion over 24 h was dose-dependently increased and displayed saturation kinetics at >25 mg. No significant changes in the levels of serum glucose and urine electrolytes were found following a single or multiple doses of henagliflozin administration. IMPLICATIONS: Henagliflozin was well tolerated and showed predictable PK/PD profiles in these healthy subjects. Henagliflozin did not affect blood glucose level or urinary electrolyte excretion. It is best characterized for once-daily administration with a maximum dose of 25 mg. ChinaDrugTrials.org.cn identifiers: CTR20131986 and CTR20140132.

Effects of Food on the Pharmacokinetic Properties and Mass Balance of Henagliflozin in Healthy Male Volunteers.

PURPOSE: Henagliflozin is a highly selective and effective sodium glucose co-transporter (SGLT)-2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the effects of meal intake on the pharmacokinetic properties of henagliflozin, and to understand the excretion pathways of henagliflozin in humans. METHODS: In this Phase I, randomized, open-label, single-dose, two-period crossover study, 12 healthy male Chinese volunteers were randomized to receive either henagliflozin 10 mg in the fasted condition followed by henagliflozin 10 mg in the fed condition, or the reverse schedule, with the two administrations separated by a washout period of at least 7 days. Samples of blood, urine, and feces were collected and analyzed for the investigation of the pharmacokinetic profile and excretion pathways in the fasted and fed conditions. Any adverse events that occurred throughout the study were recorded for tolerability assessment. FINDINGS: After the administration of a single oral dose of henagliflozin, mean (SD) plasma AUC0-∞ and Cmax were 1200 (274) h · ng/mL and 179 (48.8) ng/mL, respectively, in the fasted state and were decreased to 971 (245) h · ng/mL and 115 (34.2) ng/mL in the fed state. The fed/fasted ratios (90% CIs) of the geometric mean values of Cmax, AUC0-t, and AUC0-∞ were 64% (54%-76%), 80% (76%-85%), and 80% (76%-85%), respectively. The median (range) Tmax was prolonged from 1.5 (1-3) hours in the fasted condition to 2 (1.5-6) hours in the fed condition. Mass-balance testing revealed that henagliflozin was eliminated primarily as the parent drug in feces and as glucuronide metabolites in urine. In the fasted state, the cumulative excretion percentages of the parent drug and its metabolites to dose in feces and urine were 40.6% and 33.9%, respectively. The values in the fed condition were changed to 50.4% and 25.5%, respectively. These findings suggest that postprandial administration decreases the absorption rate and the extent of henagliflozin exposure in humans, but has no effect on the metabolism or elimination of the drug. IMPLICATIONS: In the present study, the consumption of a high-fat meal prior to henagliflozin administration was associated with reductions in AUC0-∞ and Cmax of 19.4% and 36.4%, respectively. However, based on the analysis of the pharmacokinetic/pharmacodynamic findings on henagliflozin, this slight change may not have clinical significance. Mass balance of henagliflozin in humans was achieved with ∼75% of the administered dose recovered in excretions within 4 days after administration whether in the fasted or fed state. These findings suggest that henagliflozin tablets can be administered with or without food.