Zemidapa Mechanism of Action

Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose lowering drugs. ATC code: A10BD30.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Zemidapa combines two anti-hyperglycemic medicinal products with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: gemigliptin tartrate sesquihydrate, a DPP-4 inhibitor, and dapagliflozin, a SGLT 2 inhibitor.
Clinical efficacy and safety: Glycemic control: Gemigliptin add-on to metformin and dapagliflozin combination therapy: In a 24-week, multicenter, randomized, placebo-controlled, parallel-group, double-blind study, gemigliptin 50 mg was compared to placebo once daily as add-on therapy in subjects with inadequate glycemic control type 2 diabetes mellitus (7.0% ≤ HbA1c ≤ 11.0%) in combination with metformin (≥1,000 mg/day) and dapagliflozin (10 mg/day). At week 24, the adjusted mean change in HbA1c from baseline was -0.86% for the gemigliptin 50 mg group and -0.20% for the placebo group. Gemigliptin 50 mg resulted in statistically significant (p-value <0.0001) reductions in HbA1c compared to placebo at week 24 (adjusted mean change difference: -0.66% (95% CI: -0.80%, -0.52%).
Dual add-on therapy with gemigliptin and dapagliflozin in patients with inadequate glycemic control on metformin: In a 24-week, multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group study, dual add-on therapy with gemigliptin 50 mg and dapagliflozin 10 mg was compared to each add-on therapy with gemigliptin 50 mg or dapagliflozin 10 mg once daily in subjects with inadequate glycemic control type 2 diabetes mellitus (7.0% ≤ HbA1c ≤ 11.0%) on metformin (≥1,000 mg/day) alone regarding efficacy and safety.
At week 24, the adjusted mean change in HbA1c from baseline were -1.34%, -0.90% and -0.78%, respectively, in the gemigliptin and dapagliflozin group, in either gemigliptin or dapagliflozin group. The dual add-on therapy with gemigliptin and dapagliflozin resulted in statistically significant (p-value <0.0001) reductions in HbA1c compared to the add-on therapy with either gemigliptin or dapagliflozin at week 24 (adjusted mean change difference: -0.44% (95% CI: -0.58%, -0.31%).
Gemigliptin: Mechanism of Action: Gemigliptin is a member of a class of oral anti-hyperglycemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors, which enhances the level of active incretin hormones, including GLP-1 and GIP, thereby reducing blood glucose levels. Active GLP-1 and GIP promote insulin production and release from pancreatic beta cells. GLP-1 also lowers the secretion of glucagon from pancreatic alpha cells, thereby resulting in a decreased hepatic glucose production. However, these incretins are rapidly degraded by the DPP-4. Gemigliptin selectively inhibits DPP-4 activity, enhancing prolonged activation of incretin hormones. Gemigliptin demonstrates >3,400-fold and >9,500-fold selectivity versus DPP-9 and DPP-8, respectively.
Clinical Efficacy and Safety: Over 2,200 patients with type 2 diabetes have been included in randomized, controlled clinical trials. Overall, gemigliptin improved glycemic control when used as monotherapy or in combination treatment.
Dapagliflozin: Mechanism of action: Dapagliflozin is a reversible competitive inhibitor of sodium glucose co-transporter 2 (SGLT2) with nanomolar potency that improves glycaemic control in patients with type 2 diabetes mellitus and provides cardio-renal benefits. Inhibition of SGLT2 by dapagliflozin reduces reabsorption of glucose from the glomerular filtrate in the proximal renal tubule with a concomitant reduction in sodium reabsorption leading to urinary excretion of glucose and osmotic diuresis. Dapagliflozin therefore increases the delivery of sodium to the distal tubule which is believed to increase tubuloglomerular feedback and reduce intraglomerular pressure. Secondary effects of SGLT2 inhibition with dapagliflozin also include a modest reduction in blood pressure, reduction in body weight, and an increase in haematocrit.
The cardio-renal benefits of dapagliflozin are not solely dependent on the blood glucose lowering effect and not limited to patients with diabetes. In addition to the osmotic diuretic and related hemodynamic actions of SGLT2 inhibition, potential secondary effects on myocardial metabolism, ion channels, fibrosis, adipokines and uric acid may be mechanisms underlying the cardio-renal beneficial effects of dapagliflozin. Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. This glucose excretion (glucuretic effect) is observed after the first dose, is continuous over the 24-hour dosing interval, and is sustained for the duration of treatment. The amount of glucose removed by the kidney through this mechanism is dependent upon the blood glucose concentration and GFR. Thus, in subjects with normal glucose, dapagliflozin has a low propensity to cause hypoglycaemia. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycaemia. Dapagliflozin acts independently of insulin secretion and insulin action. Over time, improvement in beta cell function (HOMA-2) has been observed in clinical studies with dapagliflozin.
The majority of the weight reduction was body fat loss, including visceral fat rather than lean tissue or fluid loss as demonstrated by dual energy X-ray absorptiometry (DXA) and magnetic resonance imaging.
SGLT2 is selectively expressed in the kidney. Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is approximately 1,000-3,000 times more selective for SGLT2 vs. SGLT1, the major transporter in the gut responsible for glucose absorption.
Pharmacodynamic effects: Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin. Approximately 70 g of glucose was excreted in the urine per day (corresponding to 280 kcal/day) at a dapagliflozin dose of 10 mg/day in patients with type 2 diabetes mellitus for 12 weeks. This glucose elimination rate approached the maximum glucose excretion observed at 20 mg/day dose of dapagliflozin. Evidence of sustained glucose excretion was seen in patients with type 2 diabetes mellitus given dapagliflozin 10 mg/day for up to 2 years.
This urinary glucose excretion with dapagliflozin also results in osmotic diuresis and increases in urinary volume. Urinary volume increases in patients with type 2 diabetes mellitus treated with dapagliflozin 10 mg were sustained at 12 weeks and amounted to approximately 375 mL/day. The increase in urinary volume was associated with a small and transient increase in urinary sodium excretion that was not associated with changes in serum sodium concentrations.
Urinary uric acid excretion was also increased transiently (for 3-7 days) and accompanied by a reduction in serum uric acid concentration. At 24 weeks, reductions in serum uric acid concentrations ranged from 18.3 to 48.3 µmol/L.
Pharmacokinetics: Zemidapa: A bioequivalence study in healthy subjects demonstrated that the Zemidapa combination tablets are bioequivalent to co-administration of gemigliptin and dapagliflozin as individual tablets.
The effects of food on pharmacokinetics of Zemidapa combination tablets were similar to the known food effects of gemigliptin or dapagliflozin as individual tablets.
Gemigliptin: Absorption: Following a single oral administration of gemigliptin to healthy subjects, gemigliptin was rapidly absorbed, with T_max occurring 1 to 5 hours post-dose. At the recommended dose of 50 mg, C_max and AUC were 62.7 ng/mL and 743.1 ng·hr/mL, respectively. The system exposure was increased in a dose-proportional manner in the range of 50~400 mg.
Distribution: In vitro human plasma protein binding is 29% for gemigliptin and 35%~48% for the metabolites including the major active metabolite.
Biotransformation: The responsible enzyme for the metabolism of gemigliptin is CYP3A4. In plasma, gemigliptin and the major metabolite (LC15-0636) accounted for 65%~100% and 9%~18% of the sample radioactivity. LC15-0636, a hydroxylated metabolite of gemigliptin, is pharmacologically active and two times more potent than gemigliptin. In vitro studies indicated that gemigliptin is not an inhibitor of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A4 and is not an inducer of CYP1A2, 2C8, 2C9, 2C19, or 3A4. Therefore, gemigliptin is considered unlikely to cause interactions with other drugs that utilize these metabolic pathways.
Elimination: Following oral administration of [¹⁴C] gemigliptin to healthy subjects, the administered radioactivity was recovered in feces (27%) or urine (63%). The elimination half-life after oral administration is approximately 17 hr and 24 hr for gemigliptin and LC15-0636, respectively.
Renal Impairment: The influence of renal impairment on the pharmacokinetics of gemigliptin has been evaluated. In patients with mild (CrCl: 50-80 mL/min), moderate (CrCl: 30-50 mL/min), severe (CrCl: <30 mL/min) and end stage renal disease (on hemodialysis), AUC_inf increased 1.20-, 2.04-, 1.50- and 1.69-fold for gemigliptin and 0.91-, 2.17-, 3.07- and 2.66-fold for LC15-0636, when compared with the normal kidney function group. Overall active moiety, the sum of gemigliptin and LC15-0636, was increased less than or approximately 2-fold in patients with moderate and severe renal impairment.
Hepatic Impairment: The influence of hepatic impairment on the pharmacokinetics of gemigliptin has been evaluated. In mild and moderate hepatic impairment, exposure to gemigliptin (AUC) after single dosing was 50% and 80% higher than in healthy subjects. Formation of LC15-0636, a metabolite of gemigliptin, was only slightly affected by mild hepatic impairment (5% to 10% lower), while in moderate hepatic impairment, formation of LC15-0636 was about 30% lower compared to healthy subjects. Urinary excretion parameters were not markedly influenced by hepatic impairment, so the decrease in total clearance of gemigliptin observed in hepatic impairment is due to a decreased metabolization rate of gemigliptin. Half-lives of gemigliptin and of LC15-0636 were slightly increased in hepatic impairment.
In mild and moderate hepatic impairment, inhibition of DPP-4 was slightly decreased compared to healthy subjects (5% to 10%), however, neither the effect on AUEC nor on E_max of DPP-4 inhibition was statistically significant.
It is expected that dose adjustment would not be required in mild and moderate hepatic impairment based on the efficacy and safety profile of gemigliptin in clinical and non-clinical studies.
Gender: No dose adjustment is necessary based on gender. The differences in C_max and AUC_inf were not clinically significant.
Race: Caucasian subjects demonstrated 28% decrease in C_max and 5% decrease in AUC_inf when compared with Korean subjects.
Dapagliflozin: Absorption: Dapagliflozin was rapidly and well absorbed after oral administration and can be administered with or without food. Maximum dapagliflozin plasma concentrations (C_max) were usually attained within 2 hours after administration in the fasted state. The C_max and AUC values increased proportional to the increment in dapagliflozin dose. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Food had relatively modest effects on the pharmacokinetics of dapagliflozin in healthy subjects. Administration with a high-fat meal decreased dapagliflozin C_max by up to 50% and prolonged T_max by approximately 1 hour, but did not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful.
Distribution: Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in various disease states (e.g. renal or hepatic impairment).
Metabolism: Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin 3-O-glucuronide. Dapagliflozin 3-O-glucuronide, with a molar plasma AUC 52% higher than that of dapagliflozin itself at the clinical dose, is an inactive metabolite and does not contribute to the glucose lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, and CYP mediated metabolism was a minor clearance pathway in humans.
Excretion: Dapagliflozin and related metabolites are primarily eliminated via urinary excretion, of which less than 2% is unchanged dapagliflozin. After oral administration of 50 mg [¹⁴C] dapagliflozin dose, 96% was recovered, 75% in urine and 21% in faeces. In faeces, approximately 15% of the dose was excreted as parent drug. The mean plasma terminal half-life (t_½) for dapagliflozin was 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects.
Renal impairment: Dapagliflozin should not be used in patients with eGFR persistently <45 mL/min/1.73 m². At steady-state (20 mg once-daily dapagliflozin for 7 days), patients with type 2 diabetes and mild, moderate or severe renal impairment (as determined by iohexol clearance) had mean systemic exposures of dapagliflozin that were 32%, 60% and 87% higher, respectively, than those of patients with type 2 diabetes and normal renal function. At dapagliflozin 20 mg once-daily, higher systemic exposure to dapagliflozin in patients with type 2 diabetes mellitus and renal impairment did not result in a correspondingly higher renal glucose clearance or 24-hour glucose excretion. The renal glucose clearance and 24-hour glucose excretion were lower in patients with moderate or severe renal impairment as compared to patients with normal and mild renal impairment. The steady-state 24-h urinary glucose excretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day was excreted by patients with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. There were no differences in the protein binding of dapagliflozin between renal impairment groups or compared to healthy subjects. The impact of haemodialysis on dapagliflozin exposure is not known.
Hepatic impairment: A single dose (10 mg) dapagliflozin clinical pharmacology study was conducted in patients with mild, moderate or severe hepatic impairment (Child-Pugh classes A, B, and C, respectively) and healthy matched controls in order to compare the pharmacokinetic characteristics of dapagliflozin between these populations. There were no differences in the protein binding of dapagliflozin between hepatic impairment groups or compared to healthy subjects. In patients with mild or moderate hepatic impairment mean C_max and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences were not considered to be clinically meaningful and no dose adjustment from the proposed usual dose of 10 mg once daily for dapagliflozin is proposed for these populations. In patients with severe hepatic impairment (Child-Pugh class C) mean C_max and AUC of dapagliflozin were up to 40% and 67% higher than matched healthy controls, respectively.
Elderly: The effect of age (young: ≥18 to <40 years [n=105] and elderly: ≥65 years [n=224]) was evaluated as a covariate in a population pharmacokinetic model and compared to patients ≥40 to <65 years using data from healthy subject and patient studies. The mean dapagliflozin systemic exposure (AUC) in young patients was estimated to be 10.4% lower than in the reference group [90% CI: 87.9, 92.2%] and 25% higher in elderly patients compared to the reference group [90% CI: 123, 129%]. However, an increased exposure due to age-related decrease in renal function can be expected. There are insufficient data to draw conclusions regarding exposure in patients >70 years old.
Gender: Gender was evaluated as a covariate in a population pharmacokinetic model using data from healthy subject and patient studies. The mean dapagliflozin AUCss in females (n=619) was estimated to be 22% higher than in males (n=634) (90% CI; 117,124).
Race: Race (White, Black [African descent], or Asian) was evaluated as a covariate in a population pharmacokinetic model using data from healthy subject and patient studies. Differences in systemic exposures between these races were small. Compared to Whites (n=1147), Asian subjects (n=47) had no difference in estimated mean dapagliflozin systemic exposures [90% CI range; 3.7% lower, 1% higher]. Compared to Whites, Black (African descent) subjects (n=43) had 4.9% lower estimated mean dapagliflozin systemic exposures [90% CI range; 7.7% lower, 3.7% lower].
Body Mass Index: In a population pharmacokinetic analysis using data from healthy subjects and patient studies, systemic exposures in high body weight subjects (≥120 kg, n=91) were estimated to be 78.3% [90% CI: 78.2, 83.2%] of those of reference subjects with body weight between 75 and 100 kg. This difference is considered to be small, therefore, no dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in patients with type 2 diabetes mellitus with high body weight (≥120 kg) is recommended.
Subjects with low body weights (<50 kg) were not well represented in the healthy subject and patient studies used in the population pharmacokinetic analysis. Therefore, dapagliflozin systemic exposures were simulated with a large number of subjects. The simulated mean dapagliflozin systemic exposures in low body weight subjects were estimated to be 29% higher than subjects with the reference group body weight. This difference is considered to be small and based on these findings no dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in patients with type 2 diabetes mellitus with low body weight (<50 kg) is recommended.
Toxicology: Preclinical safety data: No animal studies have been conducted with Zemidapa.
The following data are findings in studies performed with gemigliptin or dapagliflozin individually.
Gemigliptin: A two-year carcinogenicity study was conducted in male and female rats given oral doses of gemigliptin of 50, 150, and 450 mg/kg/day. No evidence of carcinogenicity with gemigliptin was found in either male or female rats. This dose results in exposures approximately 129~170 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 50 mg/day based on AUC comparisons. A 6-month carcinogenicity study has been performed in TgrasH2 transgenic mice at doses of 200, 400, and 800 mg/kg/day in males and 200, 600, 1,200 mg/kg/day in females. There was no evidence of carcinogenicity with gemigliptin at a dose of 1,200 mg/kg/day, approximately 87 times the human exposure at the maximum recommended daily dose.
Genotoxicity assessments in the Ames test, chromosomal aberrations test and in vivo micronucleus tests in mice and rats were negative.
The fertility of gemigliptin was not affected at dose of 800 mg/kg/day in rats. Gemigliptin was not teratogenic up to 200 mg/kg/day in rats and 300 mg/kg/day in rabbits, which are respectively 83 and 153 times human exposure at the MRHD of 50 mg/day.
Gemigliptin at dose of 800 mg/kg/day in rat, approximately 264 times human exposure at the MRHD of 50 mg/day, increased the incidence of fetus cleft palate malformation, dilated renal pelvis, misshapen thymus and sternoschisis, with increasing dose.
Dapagliflozin: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and fertility. Dapagliflozin did not induce tumours in either mice or rats at any of the doses evaluated in two-year carcinogenicity studies.