Zemimet SR Mechanism of Action

Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose lowering drugs. ATC code: A10BD18.
PHARMACOLOGY: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Zemimet SR 50/1000 mg 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 dipeptidyl peptidase 4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.
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: The benefit of administering gemigliptin in patients with type 2 diabetes and the risk associated with this treatment has been evaluated in the clinical program conducted in total 1473 subjects randomized in 6 clinical trials.
Gemigliptin dose finding: The efficacy and safety of gemigliptin monotherapy was evaluated in a placebo-controlled Phase II study of 12 week duration. The mean change in HbA1c from baseline at Week 12 was -0.98%, -0.74% and -0.78% (when adjusted with placebo data, -0.92%, -0.68% and -0.72%) at dosage levels of 50 mg, 100 mg and 200 mg, respectively.
Monotherapy: The efficacy and safety of gemigliptin monotherapy was evaluated in a placebo-controlled Phase III study of 24 week duration. The analysis of covariance for HbA1c change from baseline at Week 24 (W24 - W0) demonstrated that placebo-subtracted mean HbA1c reduction from baseline was -0.705% [95% CI -1.041 to -0.368]. Therefore, the clinical efficacy of gemigliptin was demonstrated to be superior to that of the placebo group. The study was extended through Week 52. In the extended part of the study, an analysis of HbA1c change from baseline revealed consistent glycemic control effect of gemigliptin over a period of 52 weeks. Further decrease in HbA1c was observed with continued treatment of gemigliptin 50 mg in the latter 28 weeks and the degree of change from baseline at Week 52 (-0.87%) was still clinically and statistically significant (p<0.0001).
Gemigliptin as add-on to metformin therapy: The efficacy and safety of gemigliptin add-on combination therapy was evaluated in an active-controlled Phase III study of 24 week duration. The analysis of covariance for HbA1c change from baseline at Week 24 (W24 - W0) demonstrated that the between-group difference (each regimen group of gemigliptin-sitagliptin group) in the least square mean change from baseline was 0.056% [90% CI -0.117 to 0.23] for 50 mg, qd group and 0.04% [90% CI -0.121 to 0.2] for 25 mg, bid group. Therefore, the clinical efficacy of gemigliptin was demonstrated to be at least comparable with that of the comparator, sitagliptin. The study was extended through Week 52. In the extended part of the study, the change in HbA1c from baseline was clinically and statistically significant (p<0.0001) throughout the duration of 52 weeks in all treatment groups. The decrease in HbA1c was most prominent at Week 6 followed by further gradual decrease thereafter. Decreased HbA1c level was well maintained in all three groups during the extended 28 weeks.
Gemigliptin as add-on to a combination of metformin and sulfonylurea therapy: The efficacy and safety of gemigliptin triple combination therapy with metformin and sulfonylurea was evaluated in a placebo-controlled Phase III study of 24 week duration. Analysis of covariance (ANCOVA) was conducted using the HbA1c value at baseline as a covariate and including the glimepiride reduction as a factor in relation to the change in HbA1c at Week 24. In the main population for analysis, the least square mean of the HbA1c change at Week 24 after study treatment was -0.877±0.166% (p<0.0001) in gemigliptin group and -0.012±0.179% (p=0.9476) in the placebo group, showing a significant reduction compared to the baseline in the gemigliptin group. As the 95% CI for the difference in change between the treatment groups was (-1.092,-0.638), i.e., its upper limit was less than 0, the superiority of the gemigliptin group was demonstrated.
Gemigliptin and metformin as initial therapy: The efficacy and safety of gemigliptin initial combination therapy with metformin was evaluated in an active-controlled Phase III study of 24 week duration. For the change of HbA1c from baseline at Week 24, analysis of covariance was performed. As a result, 95% CI for between group difference in least square means of HbA1c changes in combination therapy group and each monotherapy group were (-1.02,-0.63) in combination therapy group compared with gemigliptin group and (-0.82,-0.41) in combination therapy group compared with metformin group, respectively. This showed that the upper limits of both CI were less than zero (p<0.001), confirming superiority of the combination therapy group.
Glycemic variability of gemigliptin versus sitagliptin or glimepiride: The efficacy of gemigliptin on MAGE (mean amplitude of glycemic excursions) and safety of initial combination therapy of gemigliptin versus sitagliptin or glimepiride with metformin in patients with type 2 diabetes was evaluated in a multicenter, randomized, active-controlled, parallel group, open-label, exploratory study. The change in MAGE at Week 12 was -43.11mg/dL, -38.27mg/dL and -21.74mg/dL in the gemigliptin and metformin group, sitagliptin and metformin group and glimepiride and metformin group, respectively. In the test result between the groups, DPP-4 inhibitors, i.e., the gemigliptin and metformin group and sitagliptin and metformin group, reduced the MAGE compared to sulfonylurea, i.e., glimepiride and metformin group (gemigliptin: p=0.0306, sitagliptin: p=0.0292).
The data collected in clinical studies demonstrated that gemigliptin was well tolerated and displayed an overall safety profile that is at least comparable with that of the comparator.
Metformin: Mechanism of action: Metformin is a biguanide with anti-hyperglycemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia.
Metformin may act via three mechanisms: by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilisation; by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).
In humans, independently of its action on glycemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels.
Clinical efficacy and safety: The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed: a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034; a significant reduction of the absolute risk of any diabetes-related mortality: metformin 7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017; a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021); a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).
Pharmacokinetics: Zemimet SR 50/1000 mg: A bioequivalence study in healthy subjects demonstrated that the Zemimet SR 50/1000 mg combination tablets are bioequivalent to co-administration of gemigliptin and metformin hydrochloride as individual tablets.
The effects of food on pharmacokinetics of Zemimet SR 50/1000 mg combination tablets were similar to the known food effects of gemigliptin or metformin as individual tablets.
Absorption: After administration of Zemimet SR 50/1000 mg as a single oral dose to healthy male subjects under fed conditions, the T_max for gemigliptin is reached in 3 hr, C_max and AUC_last for gemigliptin were 67.78 ng/mL and 707.57 ng·hr/mL, respectively. The T_max for metformin is reached in 7 hr, C_max and AUC_last for metformin were 1,297.09 ng/mL and 14,726.8 ng·hr/mL, respectively.
After administration of Zemimet SR 50/1000 mg as a single oral dose to healthy subjects under fasting conditions, the T_max for gemigliptin is reached in 3 hr. C_max and AUC_last for gemigliptin were 59.3046 ng/mL and 807.76 ng·hr/mL, respectively. The T_max for metformin is reached in 4 hr, C_max and AUC_last for metformin were 1,301.1621 ng/mL and 10,179.13 ng·hr/mL, respectively.
Effect of Food: After administration of Zemimet SR 50/1000 mg as a single-dose to healthy subjects under fasting and fed conditions, for gemigliptin and metformin, the values of C_max were 41% and 39% higher in fed conditions than in fasting conditions, respectively. However, the values of AUC_last was not significantly different between fasting and fed conditions, and also the 90% confidence intervals were within bioequivalence ranges. Hence, a weak pharmacokinetic interaction of Zemimet SR tab 50/1000 mg by food effect was observed, however, the interaction is not clinically significant.
The following statements reflect the pharmacokinetic properties of the individual active substances of Zemimet SR 50/1000 mg.
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 clinical 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. When co-administration of a high-fat meal with gemigliptin, food slightly delayed the absorption of gemigliptin, decreased the C_max by 39% but did not affect the AUC. These changes were not considered to be clinically meaningful.
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.
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 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.
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.
Metformin: Absorption: After an oral dose of metformin, T_max is reached in 2.5 h. Absolute bioavailability of a 500 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in feces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 1 µg/mL. In controlled clinical trials, maximum metformin plasma levels (C_max) did not exceed 4 µg/mL, even at maximum doses.
Interaction with food: Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min prolongation of time to peak plasma concentration was observed. The clinical relevance of this decrease is unknown.
Distribution: Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean V_d ranged between 63-276 L.
Biotransformation: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
Toxicology: Preclinical safety data: No animal studies have been conducted with Zemimet SR 50/1000 mg. Potential toxicity and reversibility to the combination of gemigliptin and metformin was evaluated in rats administered co-suspended formulation.
In the oral rat single-dose study, the approximate lethal dose levels were considered to be greater than 150 mg/kg and 1500 mg/kg for gemigliptin and metformin, respectively.
In 3-month toxicity studies in which rats were treated with either metformin or gemigliptin alone, or a combination of metformin and gemigliptin, no additional toxicity was observed from the combination. The NOAEL in these studies was observed at exposures to gemigliptin of approximately 23~26 times the human exposure (50 mg) and to metformin of approximately 13~14 times the human exposure (1000 mg).
The following data are findings in studies performed with gemigliptin or metformin 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, 1200 mg/kg/day in females. There was no evidence of carcinogenicity with gemigliptin at a dose of 1200 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 rat. 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.
In animal studies, gemigliptin was excreted at a ratio of 1: 4~10 in plasma and milk in rats. Therefore, Zemimet SR 50/1000 mg should not be administered in nursing woman.
Metformin: Preclinical data for metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.