A contrast in safety,pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the γ-secretase inhibitor avagacestat

AIM

To evaluate the single dose pharmacokinetics, pharmacodynamics, and preliminary tolerability of the γ-secretase inhibitor BMS-708163 (avagacestat) in young and elderly men and women.

METHODS

All subjects received double-blinded administration of a single 50 mg dose of avagacestat in capsule form or matching placebo. Main evaluations included pharmacokinetics, safety, plasma amyloid-β (Aβ)_1–40 concentratios and exploration of Notch biomarkers.

RESULTS

Avagacestat 50 mg capsule was well tolerated and rapidly absorbed among young and elderly subjects, with a median t_max between 1 and 2 h post dose and an average half-life between 41 and 71 h. In general, subjects aged 75 years or more had higher AUC(0,∞) values than those aged less than 75 years. An exploratory analysis of Aβ_1–40 serum concentrations showed a pattern of decreasing concentrations over the first 4–6 h followed by a rise above baseline that was maintained until the end of the assessment period. Adverse events were generally mild, occurring more frequently in elderly subjects, with no observed difference between subjects receiving avagacestat and placebo. No dose limiting gastrointestinal effects of avagacestat were observed and exploratory biomarkers of Notch inhibition did not change significantly.

CONCLUSIONS

The favourable safety profile and pharmacokinetic effects of avagacestat in this study support its continued development, especially in the target population of elderly subjects with mild cognitive impairment or Alzheimer''s disease.     

Safety, tolerability, and pharmacokinetics of etamicastat, a novel dopamine-β-hydroxylase inhibitor, in a rising multiple-dose study in young healthy subjects

Background: Activation of the sympathetic nervous system is an important feature in hypertension and congestive heart failure. A strategy for directly modulating sympathetic nerve function is to reduce the biosynthesis of norepinephrine (noradrenaline) via inhibition of dopamine-β-hydroxylase (DβH).Objective: To assess the safety, tolerability, and pharmacokinetics of etamicastat (BIA 5–453), a new DβH inhibitor, following repeated dosing.Methods: A double-blind, randomized, placebo-controlled study was conducted in healthy young male volunteers. Participants received once-daily doses of placebo or etamicastat 25, 50, 100, 200, 400, or 600 mg, for 10 days.Results: Etamicastat underwent N-acetylation to its metabolite BIA 5–961. Etamicastat and BIA 5–961 maximum concentrations were achieved at 1–3 and 2–4 hours, respectively, after dosing. Elimination half-lives ranged from 18.1 to 25.7 hours for etamicastat and 6.7 to 22.5 hours for BIA 5–961. Both etamicastat and BIA 5-961 followed linear pharmacokinetics. The extent of systemic exposure to etamicastat and BIA 5–961 increased in an approximately dose-proportional manner, and steady-state plasma concentrations were attained up to 9 days of dosing. Etamicastat accumulated in plasma following repeated administration. The mean observed accumulation ratio was 1.3–1.9 for etamicastat and 1.3–1.6 for BIA 5–961. Approximately 40%of the etamicastat dose was recovered in urine in the form of parent compound and BIA 5–961. There was a high variability in pharmacokinetic parameters, attributable to different N-acetyltransferase-2 (NAT2) phenotype. Urinary excretion of norepinephrine decreased following repeated administration of etamicastat. Etamicastat was generally well tolerated. There was no serious adverse event or clinically significant abnormality in clinical laboratory tests, vital signs, or ECG parameters.Conclusion: Etamicastat was well tolerated. Etamicastat undergoes N-acetylation, which is markedly influenced by NAT2 phenotype. NAT2 genotyping could be a step toward personalized medicine for etamicastat.Trial Registration: EudraCT No. 2007-004142-33     

Hospitalization period and direct medical cost in patients using warfarin or novel oral anti‐coagulants after a cerebral embolism

International Journal of Clinical Pharmacy - Background Warfarin has been used in Japan for a long time in patients after cerebral embolism to prevent recurrence. Recently, several novel oral...     

Multiple-Dose Safety, Pharmacokinetics, and Pharmacodynamics of the μ-Opioid Receptor Inverse Agonist GSK1521498

The endogenous opioid system and μ-opioid receptors in particular have been demonstrated to play a fundamental role in hedonic and motivational behaviors reinforced by rewards. In healthy participants, the authors examined the multiple-dose safety, pharmacokinetic, and secondary pharmacodynamic profile of GSK1521498, a μ-opioid receptor inverse agonist that is being developed for treatment of disorders of compulsive consumption. Clinically relevant doses of GSK1521498 (2, 5, and 10 mg) following once-daily administration for 10 days, were well tolerated with no clinically relevant changes in vital signs, chemistry, or hematologic parameters and with a favorable neuropsychiatric profile. Following oral administration, median first time to reach maximum observed plasma concentration for GSK1521498 occurred 2 to 5 hours after dosing, with individual values ranging from 1 to 8 hours. Systemic exposure to GSK1521498 (area under the curve [0-∞] and maximum observed plasma concentration) increased in a slightly greater-than-dose-proportional manner, and steady-state plasma levels were reached within approximately 7 days. The secondary pharmacodynamic effects of GSK1521498 on cognition and pain threshold and tolerance were dose related, with mild to moderate impairments in measures of attention and reductions of pressure pain threshold and tolerance at the highest dose. These findings provide encouraging safety, tolerability, and pharmacokinetic data in support of the continued clinical development of GSK1521498.     

Studies on the pharmacokinetics and metabolism of a γ-secretase inhibitor BMS-299897, and exploratory investigation of CYP enzyme induction

1. BMS-299897 is a γ-secretase inhibitor that was effective in reducing amyloid β-peptide (Aβ) in transgenic mice and guinea pigs. Therefore, pharmacokinetic and drug metabolism studies were conducted in animals to support its clinical development. The compound appeared to have low to intermediate total body clearance and was orally bioavailable (24–100%). The oral absorption of BMS-299897 from solid dosage forms appeared to be dissolution rate-limited.

2. BMS-299897 was distributed into extravascular space (V_ss?≥?1.3 l kg^?1), including brain (brain-to-plasma ratio?=?0.13–0.50). BMS-299897 appeared to be a P-glycoprotein (P-gp) substrate as the brain-to-plasma ratio was two-fold higher in the mdr1a knockout mouse as compared with the wild-type.

3. Apparent autoinduction by BMS-299897 was observed in murine and rat efficacy and toxicity studies. In vitro, BMS-299897 was a weaker inducer of cytochrome P450 3A4 (CYP3A4) and a weaker transactivator of human pregnane X receptor (hPXR) as compared with rifampicin. Induction of human UGT1A and UGT2B was evaluated in primary human hepatocytes, but the results were inconclusive. A low potential for autoinduction in humans was predicted at a clinical dose of 250?mg and the prediction was consistent with the findings from a clinical multiple-dose study with BMS-299897 in probable Alzheimer’s patients.

     

Opioid receptor modulation of hedonic taste preference and food intake: a single-dose safety, pharmacokinetic, and pharmacodynamic investigation with GSK1521498, a novel μ-opioid receptor inverse agonist

Endogenous opioids and μ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a μ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selectively reduced sensory hedonic ratings of high-sugar and high-fat dairy products and caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption.     

Disposition and metabolism of [14C]-galunisertib,a TGF-βRI kinase/ALK5 inhibitor,following oral administration in healthy subjects and mechanistic prediction of the effect of itraconazole on galunisertib pharmacokinetics

1.?The disposition and metabolism of galunisertib (LY2157299 monohydrate, a TGF-βRI Kinase/ALK5 Inhibitor) was characterized following a single oral dose of 150?mg of [¹⁴C]-galunisertib (100?µCi) to six healthy human subjects.

2.?The galunisertib plasma half-life was 8.6?h, while the ¹⁴C half-life was 10.0?h. Galunisertib was abundant in circulation (40.3% of the ¹⁴C AUC024?h), with 7 additional metabolites detected in plasma. Two metabolites LSN3199597 (M5, mono-oxidation), and M4 (glucuronide of M3) were the most abundant circulating metabolites (10.7 and 9.0% of the 14C AUC024?h respectively). The pharmacological activity of LSN3199597 was tested and found to be significantly less potent than galunisertib.

3.?The dose was recovered in feces (64.5%) and in urine (36.8%). Galunisertib was cleared primarily by metabolism, based on low recovery of parent in excreta (13.0% of dose). Due to the slow in vitro metabolism of galunisertib in suspended hepatocytes, a long term hepatocyte system was used to model the human excretion profile.

4.?Expressed cytochromes P450 and hepatocytes indicated clearance was primarily CYP3A4-mediated. Mechanistic static modeling that incorporated small non-CYP-mediated metabolic clearance and renal clearance components predicted an AUC ratio of 4.7 for the effect of itraconazole, a strong CYP3A4 inhibitor, on galunisertib.     

Effects of food on pharmacokinetics of immediate release oral formulations of aspirin,dipyrone, paracetamol and NSAIDs – a systematic review

Aims

It is common to advise that analgesics, and especially non-steroidal anti-inflammatory drugs (NSAIDs), be taken with food to reduce unwanted gastrointestinal adverse effects. The efficacy of single dose analgesics depends on producing high, early, plasma concentrations; food may interfere with this. This review sought evidence from single dose pharmacokinetic studies on the extent and timing of peak plasma concentrations of analgesic drugs in the fed and fasting states.

Methods

A systematic review of comparisons of oral analgesics in fed and fasting states published to October 2014 reporting kinetic parameters of bioavailability, time to maximum plasma concentration (t_max), and its extent (C_max) was conducted. Delayed-release formulations were not included.

Results

Bioavailability was not different between fasted and fed states. Food typically delayed absorption for all drugs where the fasting t_max was less than 4 h. For the common analgesics (aspirin, diclofenac, ibuprofen, paracetamol) fed t_max was 1.30 to 2.80 times longer than fasted t_max. C_max was typically reduced, with greater reduction seen with more rapid absorption (fed C_max only 44–85% of the fasted C_max for aspirin, diclofenac, ibuprofen and paracetamol).

Conclusion

There is evidence that high, early plasma concentrations produces better early pain relief, better overall pain relief, longer lasting pain relief and lower rates of remedication. Taking analgesics with food may make them less effective, resulting in greater population exposure. It may be time to rethink research priorities and advice to professionals, patients and the public.     

Pharmacokinetics of the oral multikinase inhibitor regorafenib and its association with real‐world treatment outcomes

Investigational New Drugs - Purpose Despite the established activity of regorafenib in metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST), and hepatocellular...     

The efficacy and safety of telaprevir – a new protease inhibitor against hepatitis C virus

Importance of the field: Hepatitis C virus (HCV) is the main agent of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma in the western world. It affects more than 170 million people worldwide. HCV treatment, based on the combination of Peg-interferon and ribavirin, is effective in about 50% of treated patients. Therefore, there is a need to develop new drugs active against HCV.

Areas covered in this review: Data were obtained by searching for all full articles on Medline and abstracts presented at major international congresses on viral hepatitis.

What the reader will gain: A review of clinical data about the efficacy and safety of telaprevir (VX-950), the HCV protease inhibitor that is in the most advanced phase of clinical development.

Take home message: Telaprevir has an acceptable pharmacokinetic profile and seems to be a potent antiviral drug against HCV, although, owing to a low genetic barrier, resistant variants emerge within a few days when used in monotherapy, thereby decreasing its efficacy. Consequently, telaprevir has been combined with pegylated-interferon and ribavirin in clinical trials. This triple combination is more effective but has a higher rate of adverse events (notably rash) than the standard of care, despite the shorter duration of therapy.     

Preclinical efficacy and safety assessment of nano-oxaliplatin oral formulation prepared by novel Fat Employing Supercritical Nano System,the FESNS®

Background: It is expected that oral cancer drug will provide ease of administration with decreased unwanted events to the patients. The purpose of this study is to prepare oral formulation of nano-oxaliplatin and examine the anticancer efficacy and safety. Nano-oxaliplatin was prepared utilizing our proprietary technology, the Fat Employing Supercritical Nano System (FESNS^®).

Result: It showed regular nanoparticles with a mean diameter of around 212?nm. When nano-oxaliplatin was orally administered in rats, the relative bioavailability of nano-oxaliplatin oral formulations was about 25–31% compared to the Eloxatin^® administered intravenously (i.v.). For antitumor activity in xenograft model, nano-oxaliplatin oral formulation (20?mg/kg, once daily) presented superior inhibition of tumor growth against Eloxatin^® (5?mg/kg, i.v. once a week). In single-dose toxicity, dead animals were observed at or above 1000?mg/kg (LD₅₀: 888.38?mg/kg for male; 725.43?mg/kg for female rats). In repeated dose toxicity, there were hematological changes observed in rats, which is a common finding in the class of cancer drugs. It was thought that the expected dose level that has cytotoxic effect without death would be 30?mg/kg in rats, which is double the dose level of Eloxatin^®.

Conclusion: Nano-oxaliplatin oral formulation changed the pharmacokinetic behavior of crude oxaliplatin, thus increasing oral bioavailability as well as its anticancer activity. In addition, single and repeated dose toxicity studies indicated that oral nano-oxaliplatin is superior in toxicity at the pharmacologically active doses compared to Eloxatin^® in rats. Nano-oxaliplatin oral formulation has potential as a novel anticancer therapy.     

Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects

Objectives There is a clinical need for safe new oral anticoagulants. The safety, tolerability, pharmacodynamics, and pharmacokinetics of BAY 59-7939—a novel, oral, direct Factor Xa (FXa) inhibitor—were investigated in this single-center, placebo-controlled, single-blind, parallel-group, multiple-dose escalation study. Methods Healthy male subjects (aged 20–45 years, body mass index 18.6–31.4 kg/m²) received oral BAY 59-7939 (n=8 per dose regimen) or placebo (n=4 per dose regimen) on days 0 and 3–7. Dosing regimens were 5 mg once, twice (bid), or three times daily, and 10 mg, 20 mg, or 30 mg bid. Results There were no clinically relevant changes in bleeding time or other safety variables across all doses and regimens. There was no dose-related increase in the frequency or severity of adverse events with BAY 59-7939. Maximum inhibition of FXa activity occurred after approximately 3 h, and inhibition was maintained for at least 12 h for all doses. Prothrombin time, activated partial thromboplastin time, and HepTest were prolonged to a similar extent to inhibition of FXa activity for all doses. Dose-proportional pharmacokinetics ( and C_max,norm) were observed at steady state (day 7). Maximum plasma concentrations were achieved after 3–4 h. The terminal half-life of BAY 59-7939 was 5.7–9.2 h at steady state. There was no relevant accumulation at any dose. Conclusions BAY 59-7939 was safe and well tolerated across the wide dose range studied, with predictable, dose-proportional pharmacokinetics and pharmacodynamics and no relevant accumulation beyond steady state. These results support further investigation of BAY 59-7939 in phase II clinical trials.     

Dose‐dependent plasma clearance of MK‐826, a carbapenem antibiotic,arising from concentration‐dependent plasma protein binding in rats and monkeys

After intravenous administration of MK‐826, a new carbapenem antibiotic, the compound exhibited nonlinear pharmaco‐kinetics in rats and monkeys. In both species, time‐averaged plasma clearance (based on total concentrations) increased about 5‐fold over the 10‐ to 180‐mg/kg dose range. MK‐826 was extensively plasma protein bound in rat and monkey plasma, and the extent of binding was concentration dependent at plasma concentrations achieved after administration of these doses. Rosenthal analysis of the plasma protein binding indicated that there were two classes of binding sites. The binding capacity of the primary site was comparable to the plasma albumin concentration, which suggested that this primary site consisted of a single site on albumin. The extent of binding of MK‐826 to rat albumin was similar to that in whole plasma. Clearance values based on unbound concentrations appeared independent of dose from 10 to 180 mg/kg, which is consistent with saturation of protein binding as the primary cause of the nonlinear pharmacokinetic behavior.     

Disposition of LY333531, a selective protein kinase C β inhibitor,in the Fischer 344 rat and beagle dog

1. Studies were conducted in the Fischer 344 rat and beagle dog to determine the disposition of LY333531 and its equipotent active des-methyl metabolite, LY338522, both potent and selective inhibitors of the β-isozyme of protein kinase C. 2. Male Fischer 344 rats and female beagle dogs received a single 5-mgkg^?1 oral dose of ¹⁴C-LY333531. Urine, faeces, bile and plasma were collected and analysed for ¹⁴C, LY333531 and LY338522. 3. LY333531 was eliminated primarily in the faeces (91% by 120 h in rat, 90% by 96h in dog). Bile contributed the majority of the radioactivity excreted in the faeces in rat (66% in the cannulated bile duct study) and a variable but significant proportion in dog. 4. Pharmacokinetics following a single 5?mg kg^?1 oral dose of ¹⁴C-LY333531 to the male rat produced C_max and AUC_0-∞ for LY333531 of 14.7 ng ml^?1 and 60.8ng h ml^?1, respectively, with a half-life of 2.5 h. LY338522 and total radioactivity showed similar profiles. 5. In the female dog at the same dose, C_max and AUC_0-∞ of LY333531 were higher, producing 245 ± 94 ng ml^?1 and 1419 ± 463ng h ml^?1, respectively, with a half-life of 5.7 h. 6. The data indicate that the disposition of LY333531 is similar in rat and dog.     

Effect of a novel phosphodiesterase type 5 inhibitor,CPD1, on carbon tetrachloride-induced liver fibrosis in mice北大核心CSCD

Aim To investigate the effects of CPD1, a novel phosphodiesterase 5 inhibitor, on liver pathological phenotype and hepatic stellate cells (HSCs) activation in hepatic fibrosis model mice caused by carbon tetrachloride ( CCl4). Methods Male C57BL/6 J mice were divided into four groups randomly ( control group, CCl4group, CCl4+ CPD1 group and CCl4+ tadalafil group) . Hepatic fibrosis model was construc¬ted by intraperitoneal injection of CCl4( twice a week) . Four weeks after CCl4injection, the mice were treated with CPD1 (2 mg kg-1• d-1) , or Tadalafil (10 mg • kg-1• d-1) by intragastric administration, respec¬tively, for four weeks. Hematoxylin-eosin staining and Sirius Red staining were used to observe the distribu¬tion of liver tissue structural lesions and fibrosis. Im-munohistochemical staining was used to detect the ex¬pression of a-smooth muscle actin ( a-SMA) and fi-bronectin. Results Compared with control group, the liver tissue structure was seriously damaged in CCl4group with many hepatocytes necrosis and inflammatory cell infiltration, indicating that liver injury occurred in the CCl4-induced hepatic fibrosis model mice. Moreo¬ver, the expressions of a-SMA increased significantly in CCl4group. Compared to CCl4group, the liver tissue damage was significantly improved in PDE5 inhibitors group,most notably, CPD1 had a better curative effect than tadalafil did. Furthermore, CPD1 inhibited the ex¬pression of a-SMA markedly and reduced the expres-sion of ECM-related proteins induced by transforming growth factor pi ( TGF-f31 ) in Lieming Xu-2 ( LX-2 ) cells. Conclusions Phosphodiesterase 5 inhibitor CPD1 strongly alleviates CCl4-induced hepatic damage by inhibiting the activation of HSCs and expression of collagen fibers. © 2023 Publication Centre of Anhui Medical University. All rights reserved.     

In vitro drug–drug interaction studies with febuxostat,a novel non-purine selective inhibitor of xanthine oxidase: plasma protein binding,identification of metabolic enzymes and cytochrome P450 inhibition

1.?The potential for drug–drug interactions with febuxostat was examined in the following three in vitro systems: the characteristics of the binding of febuxostat to human plasma proteins; identification of the cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes participating in the metabolism of febuxostat; and the potential inhibitory effects of febuxostat on typical CYP reactions.

2.?The results have shown that the presence of ibuprofen or warfarin did not change the plasma protein binding of febuxostat, and that febuxostat did not influence the plasma protein binding of ibuprofen or warfarin. These results indicate that there is little possibility that febuxostat causes a drug–drug interaction by binding to albumin.

3.?The UGT 1 and 2 families were involved in the glucuronidation, and several CYPs participated in the metabolism of febuxostat, suggesting that there is little possibility that the blood concentration of febuxostat varies widely even if febuxostat is concomitantly administered with drugs that inhibit CYP or UGT enzyme. Examination of the inhibitory effect of febuxostat on CYP enzymes suggests that febuxostat minimally inhibits the activities of any CYP.

4.?The results demonstrate that febuxostat is a novel anti-hyperuricaemia drug with low drug–drug interaction potential in clinical use.     

Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel,potent and selective inhibitor of dopamine-β-hydroxylase

1. Inhibitory modulation of sympathetic nerve function may have a favourable impact on the progression of congestive heart failure. Nepicastat is a novel inhibitor of dopamine-β-hydroxylase, the enzyme which catalyses the conversion of dopamine to noradrenaline in sympathetic nerves. The in vitro pharmacology and in vivo catecholamine modulatory effects of nepicastat were investigated in the present study.
2. Nepicastat produced concentration-dependent inhibition of bovine (IC₅₀=8.5±0.8 nM) and human (IC₅₀=9.0±0.8  nM)dopamine-β-hydroxylase. The corresponding R-enantiomer (RS-25560-198) was approximately 2–3 fold less potent than nepicastat. Nepicastat had negligible affinity (>10 μM) for twelve other enzymes and thirteen neurotransmitter receptors.
3. Administration of nepicastat to spontaneously hypertensive rats (SHRs) (three consecutive doses of either 3, 10, 30 or 100 mg kg⁻¹, p.o.; 12 h apart) or beagle dogs (0.05, 0.5, 1.5 or 5 mg kg⁻¹, p.o.; b.i.d., for 5 days) produced dose-dependent decreases in noradrenaline content, increases in dopamine content and increases in dopamine/noradrenaline ratio in the artery (mesenteric or renal), left ventricle and cerebral cortex. At the highest dose studied, the decreases in tissue noradrenaline were 47%, 35% and 42% (in SHRs) and 88%, 91% and 96% (in dogs) in the artery, left ventricle and cerebral cortex, respectively. When tested at 30 mg kg⁻¹, p.o., in SHRs, nepicastat produced significantly greater changes in noradrenaline and dopamine content, as compared to the R-enantiomer (RS-25560-198), in the mesenteric artery and left ventricle.
4. Administration of nepicastat (2 mg kg⁻¹, b.i.d, p.o.) to beagle dogs for 15 days produced significant decreases in plasma concentrations of noradrenaline and increases in plasma concentrations of dopamine and dopamine/noradrenaline ratio. The peak reduction (52%) in plasma concentration of noradrenaline and the peak increase (646%) in plasma concentration of dopamine were observed on day-6 and day-7 of dosing, respectively.
5. The findings of this study suggest that nepicastat is a potent, selective and orally active inhibitor of dopamine-β-hydroxylase which produces gradual modulation of the sympathetic nervous system by inhibiting the biosynthesis of noradrenaline. This drug may, therefore, be of value in the treatment of cardiovascular disorders associated with over-activation of the sympathetic nervous system, such as congestive heart failure.

     

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 (AUC_0–24) (GRM: 1.08; CI: 1.05, 1.10) and peak plasma concentration (C_max) (GRM: 0.99; CI: 0.92, 1.07). Reciprocally, co-administration of metformin with henagliflozin had no clinically significant on metformin AUC_0–24 (GRM: 1.09, CI: 1.02, 1.16) although there was an 11% increase in metformin C_max (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.