Trajenta Linagliptin Tablets - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Trajenta Linagliptin Tablets - Scientific Information

Manufacture: Eli Lilly and Company
Country: Canada
Condition: Type 2 Diabetes (Diabetes, Type 2)
Class: Dipeptidyl peptidase 4 inhibitors
Form: Tablets
Ingredients: linagliptin, hypromellose, titanium dioxide, talc, macrogol, iron oxide red

Pharmaceutical Information

Drug Substance

Common name: linagliptin
Chemical name: 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-
Molecular formula and molecular mass: C25H28N8O2, 472.54 g/mol
Structural formula:


Physicochemical properties: White to yellowish crystalline solid substance, very slightly soluble in water, soluble in methanol, sparingly soluble in ethanol, very slightly soluble in isopropanol and in acetone.
pKa: pKa1 = 8.6; pKa2 = 1.9
Partition Co-efficient: Log P = 1.7 (free base); Log D (pH 7.4) = 0.4
Melting Temperature: 202-209EC

Clinical Trials

Study Demographics and Trial Design

In total 6602 patients with type 2 diabetes and 453 healthy volunteers received treatment with linagliptin in the clinical program.

Table 1 Summary of patient demographics for clinical trials in specific indication

Study # Trial design Dosage, route of administration and duration Study subjects (n=number) Mean age (Range) Gender (% F/M)
Monotherapy
1218.16 Multicentre, randomised, doubleblind, placebocontrolled linagliptin 5 mg or placebo
Oral, 24 weeks
Total: 503
Linagliptin : 336
Placebo: 167
55.7 (24-79) 52/48
1218.50 Multicentre, randomised, doubleblind, placebocontrolled in metformin ineligible patients, followed by active-controlled, parallel-group comparison linagliptin 5 mg orplacebo and
linagliptin 5 mg orglimperide 1, 2, or4 mg
Oral, 18 weeks
Total: 227
Linagliptin: 151
Placebo: 76
56.5 (20-80) 61/39
Add on Combination Therapy with Metformin
1218.17 Multicentre, randomised, doubleblind, placebocontrolled linagliptin 5 mg or placebo
Oral, 24 weeks
Total: 701
Linagliptin : 524
Placebo: 177
56 (21-79) 46/54
1218.20 Multicentre, randomised, doubleblind, activecontrolled linagliptin 5 mg or glimepiride (forced titration from 1 mg to max. 4 mg)
oral, 52 weeks
Total: 1560
Linagliptin : 779
Glimepiride: 781
60 (28-80) 40/60
Add on Combination Therapy with a Sulfonylurea
1218.35 Multicentre, randomised, doubleblind, placebocontrolled linagliptin 5 mg or placebo
Oral, 18 weeks
Total: 245
Linagliptin: 161
Placebo: 84
57 (27-79) 47/53
Add on Combination Therapy with Metformin and a Sulfonylurea
1218.18 Multicentre, randomised, doubleblind, placebocontrolled linagliptin 5 mg or placebo
Oral, 24 weeks
Total: 1058
Linagliptin: 793
Placebo: 265
58 (23-79) 53/47
Open-label Long-term Extension Study
1218.40 Open-label extension trial without a control group. Patients who completed one of the 4 pivotal trial (1218.15+, 1218.16, 1218.17 or 1218.18) linagliptin 5 mg
Oral, 78 weeks
Total: 2121
Lina "old"*: 1532
Lina "new": 589
*Lina "old": patients treated with linagliptin in the preceding trials; Lina "new": patients treated with placebo in the preceding trials
57.5 (21-80) 48/52

+ Indication not approved

Study Results

Linagliptin monotherapy (BI Study 1218.16)

The efficacy and safety of linagliptin monotherapy was evaluated in a double blind placebo controlled study of 24 weeks duration. Treatment with once daily linagliptin at 5 mg provided a significant improvement in HbA1c, fasting plasma glucose (FPG), 2-hour post-prandial glucose (PPG), and a greater proportion (28%) of patients achieved a target HbA1c of < 7.0%, compared to placebo (15%) (see Table 2). Body weight did not differ significantly between the groups.

Linagliptin monotherapy for patients ineligible for metformin (BI study 1218.50)

The efficacy and safety of linagliptin monotherapy was also evaluated in patients for whom metformin therapy is inappropriate, due to intolerability or contraindication, in a double blind placebo controlled study of 18 weeks duration, followed by a 34 week safety extension period (placebo patients switched to glimepiride). Linagliptin provided significant improvements in HbA1c, fasting plasma glucose (FPG), and a greater portion of patients (28%) achieved a target HbA1c of < 7.0%, compared to placebo (15%), (Table 1). Body weight did not differ significantly between the groups during the placebo controlled 18 weeks.

Table 2 Glycemic Parameters in Placebo-Controlled Monotherapy Studies of TRAJENTA in Patients with Type 2 Diabetes
18-Week Study
(BI Study 1218.50)
24-Week Study
(BI Study 1218.16)
5 mg Placebo 5 mg Placebo
HbA1C (%) n = 147 n = 73 n = 333 n = 163
Baseline (mean) 8.11 8.04 8.0 8.0
Change from baseline (adjusted mean) -0.39 0.14 -0.44 0.25
Difference from placebo (adjusted mean) (95% CI) -0.60 (-0.88,-0.32) -0.69 (-0.85, -0.53)
Patients (%) achieving A1C <7% 41 (28%) 11 (15%) 94 (28.2%) 25 (15.3%)
FPG (mmol/L) n = 138 n = 66 n = 318 n = 149
Baseline (mean) 9.9 9.8 9.1 9.2
Change from baseline (adjusted mean) -0.74 0.4 -0.47 0.82
Difference from placebo (adjusted mean) (95% CI) -1.14 (-1.73, -0.55) -1.30 (-1.69, -0.91)
2-hour PPG (mmol/L) Data not available Data not available n = 67 n = 24
Baseline (mean) 14.33 13.56
Change from baseline (adjusted mean) -1.86 1.38
Difference from placebo (adjusted mean) (95% CI) -3.24 (-4.57, -1.91)


Figure 1 Mean HbA1C (%) over 24 Weeks with TRAJENTA and Placebo in Patients with Type 2 Diabetes (BI Study 1218.16, monotherapy patients)

Linagliptin as add on to metformin therapy (BI Study 1218.17)

The efficacy and safety of linagliptin in combination with metformin was evaluated in a double blind placebo controlled study of 24 weeks duration. Linagliptin provided significant improvements in HbA1c, fasting plasma glucose (FPG), 2-hour post-prandial glucose (PPG) and a greater portion of patients (28%) achieved a target HbA1c of < 7.0%, compared to placebo (11%) (Table 3). Body weight did not differ significantly between the groups.

Table 3 Glycemic Parameters at Final Visit (Placebo-Controlled Study) for TRAJENTA in Combination with Metformin (BI study 1218.17)
TRAJENTA 5 mg +
Metformin
Placebo + Metformin
HbA1C (%) n = 513 n = 175
Baseline (mean) 8.09 8.02
Change from baseline (adjusted mean) -0.49 0.15
Difference from placebo + metformin (adjusted mean) (95% CI) -0.64 (-0.78, -0.50)
Patients (%) achieving HbA1C <7% 145 (28.3) 20 (11.4)
FPG (mmol/L) n = 495 n = 159
Baseline (mean) 9.39 9.10
Change from baseline (adjusted mean) -0.59 0.58
Difference from placebo + metformin (adjusted mean) (95% CI) -1.17 (-1.52, -0.83)
2-hour PPG (mmol/L) n = 78 n = 21
Baseline (mean) 15.0 15.22
Change from baseline (adjusted mean) -2. 71 1.01
Difference from placebo + metformin (adjusted mean) (95% CI) -3.72 (-5.26, -2.20)


Figure 2 Mean HbA1C (%) over 24 Weeks with TRAJENTA/ Metformin and Placebo/ Metformin in Patients with Type 2 Diabetes (BI study 1218.17, add on to metformin patients)

Linagliptin as add on to a sulfonylurea therapy (BI Study 1218.35)

The efficacy and safety of linagliptin in combination with sulfonylurea was evaluated in a double blind placebo controlled study of 18 weeks duration. Linagliptin provided significant improvements in HbA1c, and a greater portion of patients (15%) achieved the target HbA1c of <7.0% compared to placebo (4%) (Table 4). Body weight did not differ significantly between the groups.

Table 4 Glycemic Parameters at Final Visit (18-Week Study) for TRAJENTA in Combination Therapy with Sulfonylurea (BI Study 1218.35)
TRAJENTA 5 mg + SU Placebo + SU
HbA1C (%) n = 158 n = 82
Baseline (mean) 8.6 8.6
Change from baseline (adjusted mean) -0.54 -0.07
Difference from placebo + SU (adjusted mean) (95% CI) -0.47 (-0.70, -0.24) --
Patients (%) achieving A1C <7% 15.2 3.7
FPG (mmol/L) n = 155 n = 78
Baseline (mean) 10.0 9.5
Change from baseline (adjusted mean) -0.46 -1.0
Difference from placebo + SU (adjusted mean) (95% CI) -0.36 (-0.96, 0.24) --

SU = sulfonylurea

Linagliptin as add on to a combination of metformin and a sulfonylurea therapy (BI Study 1218.18)

A placebo controlled study of 24 weeks in duration was conducted to evaluate the efficacy and safety of linagliptin 5 mg compared to placebo, in patients not sufficiently treated with a combination with metformin and a sulfonylurea. Linagliptin provided significant improvements in HbA1c, fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG) and a greater portion of patients (31%) achieved a target HbA1c of < 7.0% compared to placebo (9%) (Table 5). Body weight did not differ significantly between the groups.

Table 5 Glycemic Parameters at Final Visit (24-Week Study) for TRAJENTA in Combination with Metformin and Sulfonylurea (BI Study 1218.18)
TRAJENTA 5 mg +
Metformin + SU
Placebo + Metformin +
SU
HbA1C (%) n = 778 n = 262
Baseline (mean) 8.15 8.14
Change from baseline (adjusted mean) -0.72 -0.10
Difference from placebo (adjusted mean) (95% CI) -0.62 (-0.73, -0.50)
Patients n (%) achieving A1C <7% 243 (31.2) 24 (9.2)
FPG (mmol/L) n = 739 n = 248
Baseline (mean) 8.84 9.03
Change from baseline (adjusted mean) -0.26 0.45
Difference from placebo (adjusted mean) (95% CI) -0.71 (-1.0, -0.40)

SU = sulfonylurea

Linagliptin 24 month data, as add on to metformin in comparison with glimepride (BI Study 1218.20)

In a study comparing the efficacy and safety of the addition of linagliptin 5 mg or glimepiride (a sulfonylurea agent) in patients with inadequate glycemic control on metformin monotherapy, linagliptin was similar to glimepiride in reducing HbA1c, with a mean treatment difference in HbA1c from baseline to 104 weeks for linagliptin compared to glimepiride of +0.2%.

Open-label Long-term Extension Add on Combination with Various Antidiabetic Medications (BI Study 1218.40)

Data on long-term efficacy (over 12 months) is supported by the results of an open-label extension trial (1218.40) conducted in patients who completed the 24-week treatment period of 4 placebo-controlled studies (1218.15*, 1218.16, 1218.17 and 1218.18). In this extension trial, all patients received 5 mg linagliptin as monotherapy or as add-on to the background therapy they took in the previous trial. The treatment duration in this study was 78 weeks, i.e., patients who completed this study have received 5 mg for either 78 weeks (those who received placebo in the initial trial) or 102 weeks (those who received linagliptin in the initial trial). The HbA1c reduction achieved at the end of week 24 was maintained during the open label extension study.

*not an approved indication

Subgroups of the Pooled Analysis

The analysis of the influence of renal impairment (eGFR, estimated according to the MDRD formula) was limited to patients with normal renal function (≥ 90 mL/min) and patients with mild (60 to <90 mL/min) and moderate (30 to <60 mL/min) renal impairment. The number of patients with moderate renal impairment was comparatively low (n=109 in total; 29 placebo, 80 linagliptin) and the pooled analysis did not comprise any patient with severe renal impairment (<30 mL/min). The treatment effect of linagliptin in terms of adjusted mean differences to placebo in HbA1c was similar in patients with normal renal function (-0.61%), and patients with mild (-0.63%) or moderate (-0.57%) renal impairment. The p-value for the treatment-by-subgroup interaction was 0.9096. Thus, it can be concluded that mild and moderate renal impairment did not influence the treatment effect of linagliptin.

Renal Impairment

Linagliptin as add on therapy in patients with severe renal impairment, 12 week placebo controlled data (stable background) and 40 week placebo controlled extension (adjustable background)

The efficacy and safety of linagliptin was also evaluated in type 2 diabetes patients with severe renal impairment in a double blind study versus placebo where patients were on a variety of background therapies including insulin and/or oral antihyperglycemic drug. A total of 133 patients participated (linagliptin, n=68, placebo, n=65). Patients on dialysis were excluded from entry into the study. The predominant background therapy was insulin*. The study had an initial 12 week period during which background glycemic therapies were kept stable. There was a follow up 40 week period during which dose adjustments in antidiabetes background therapies were allowed.

*not an approved indication

Linagliptin provided significant improvements in HbA1c (-0.59 % change compared to placebo at week 12), from a mean baseline HbA1c of 8.2%. Improvements in A1c following treatment with linagliptin were sustained up to Week 52.

The reported safety and laboratory results were comparable between linagliptin and placebo except for the adverse events belonging to “renal impairment’ which were more frequent in linagliptin (16.2% in linagliptin vs. 6.2% in placebo), but absolute numbers were small. Since severe renal impairment was an inclusion criterion for the study, these adverse events were considered a worsening of the concomitant diagnosis at study entry. Renal function as measured by means eGFR and creatinine clearance did not change over 52 weeks treatment with linagliptin compared to placebo.

Cardiovascular risk

In a prospective meta-analysis of independently adjudicated cardiovascular events from 19 phase III clinical studies of 12-104 weeks duration (18 placebo-controlled trials of at least 12 weeks in duration, 1 glimepiride-controlled trial of 104 weeks in duration) involving 9297 patients with type 2 diabetes (2675 on placebo, 5847 on linagliptin, 775 on glimepiride), linagliptin treatment was not associated with an increase in cardiovascular risk. A composite endpoint-consisting of: the occurrence or time to first occurrence of CV death, non-fatal myocardial infarction, and non-fatal stroke, was non-significantly lower for linagliptin versus combined active and placebo comparators [Hazard ratio 0.74(95% confidence interval 0.49, 1.14)]. Comparisons of linagliptin with placebo only were not statistically significant [Hazard ratio 1.10 (95% confidence interval 0.61; 2.01)], whereas comparisons of linagliptin with glimepiride were statistically significant (Hazard ratio 0.47; 95% confidence interval 0.23; 0.97).

In the final active-controlled 104 week trial of linagliptin (N=776) versus glimepiride (N=775) as add-on therapies to metformin, the incidence of the composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke was 1.42% for linagliptin and 2.97% for glimepiride.

A prospective meta-analysis of independently adjudicated cardiovascular events from 19 phase III clinical studies of 12-104 weeks in duration (18 placebo-controlled trials of at least 12 weeks in duration, 1 glimepiride-controlled trial of 104 weeks in duration) was performed:

Endpoint Hazard Ratios (95% Confidence Intervals)
Linagliptin
(N=5847) vs.
Combined Placebo
+ Glimepiride
(N=3450)
Linagliptin
(N=5071) vs.
Placebo (N=2675)
Linagliptin
(N=776) vs.
Glimepiride
(N=775)
Expanded MACE:
- CV death
- non-fatal myocardial infarction
- non-fatal stroke
- hospitalization due to unstable angina
0.78 (0.55, 1.12) 1.09 (0.68, 1.75) 0.45 (0.23, 0.90)
Core MACE:
- CV death
- non-fatal myocardial infarction
- non-fatal stroke
0.74 (0.49, 1.14) 1.10 (0.61, 2.01) 0.47 (0.23, 0.97)

Detailed Pharmacology

Dipeptidyl Peptidase 4 (DPP-4, EC 3.4.14.5) is a membrane bound protease expressed in many tissues including kidneys, liver, intestine, lymphocytes and vascular endothelial cells. A significant level of DPP-4 activity is also observed in plasma, which likely originates from multiple tissues that express the enzyme. The most important physiological substrates of DPP-4 are the incretins Glucagon-Like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Peptide (GIP). DPP-4 catalyzes the degradation and inactivation of incretion and inhibition of DPP-4 increases the duration of these short lived endogenous incretin hormones. Both GLP-1 and GIP exert potent glucose-dependent insulinotropic actions and thereby contribute to the maintenance of post-meal glycemic control.

Linagliptin is a potent inhibitor (IC50 = 1 nM) of human Dipeptidyl Peptidase 4 (DPP-4) and exhibits high selectivity versus a variety of proteases including DPP-8 and DPP-9 (> 10,000-fold). In obese and diabetic animals (Zucker fa/fa rat, Zucker Diabetic Fatty Rat (ZDF) and db/db mice) linagliptin enhanced glucose-induced elevations of intact GLP-1 and insulin and lowered glucose levels with an ED50 of 1 mg/kg and below. These data indicate that linagliptin is an efficacious anti-diabetic drug.

The main metabolite of linagliptin CD 1790 neither inhibited DPP-4 activity nor interacted with a variety of receptors, channels and enzymes.

Linagliptin has a pharmacological profile that suggests good tolerability. Safety pharmacology studies did not indicate a risk of arrhythmia including those associated with a prolongation of the QT interval. No relevant effects on cardiovascular parameters were observed in safety pharmacology and toxicology studies in the Cynomolgus monkey at oral dosages up to and including 300 mg/kg/day (2523-fold clinical Cmax). The safety pharmacology assessment of neurological (CNS) and respiratory effects in rats after oral administration did not identify any effects on behaviour, spontaneous locomotor activity or body temperature at 600 mg/kg. Transient decreases in respiratory rate were observed at this dose. There were no effects on respiratory effects at 60 mg/kg.

Toxicology

General Toxicity

Linagliptin was well tolerated and the minimum lethal dose after a single oral dose was 1000 mg/kg in rats and mice. Repeat oral dosing was associated with lethality/moribund euthanasia at ≥600 mg/kg (> 3000 times human clinical exposure) in rats, 600 mg/kg (>3000 times human clinical exposure) in mice, 150 mg/kg (>1500 times human clinical exposure) in dogs and one monkey at 100 mg/kg (>750 times human clinical exposure). In dogs, a pseudo-allergic reaction occurred at ≥15 mg/kg and Cmax 3690 nmol/L (>300 times human clinical Cmax). The reaction was characterized by reddening and swelling of ears, circumocular region, as well as upper lips and vomiting. The reaction typically occurred 10 to 90 min post dose and then disappeared gradually and correlated reasonably with increases in circulating histamine concentrations. Linagliptin was associated with changes that appear secondary to irritation with high local concentrations of linagliptin in the GI tract after oral administration or in the biliary tract associated with excretion of drug. These ranged from minimal to slight epithelial hypertrophy/hyperplasia to ulcers and affected the gastro intestinal tract, gallbladder and biliary epithelium with or without peribiliary changes in mice (≥120 mg/kg, > 400 times human clinical exposure), rats (≥300 mg/kg, > 1500 times human clinical exposure), dogs (≥45 mg/kg, >200 times human clinical exposure) and monkeys (≥25 mg/kg, >100 times human clinical exposure). Linagliptin administration also results in metabolic effects that appear secondary to prolonged action of incretins as a result of DPP-4 inhibition. These include increased glycogen deposits in the hepatocytes of rat, mouse and monkey and decreases in cholesterol and triglycerides. The changes in the liver were not adverse at lower doses but at 300 mg/kg in the mouse and 100 mg/kg in the rat, there were either histological indication of adverse liver effects and/or increases in plasma markers for hepato-biliary perturbation. There were effects on kidney function or integrity in mouse, rat and monkey. In the monkey, there were no microscopic changes in the kidney but increases in plasma creatinine, kidney weight and urinary protein at ≥150 mg/kg(>1500 times human clinical exposure). In the rat, plasma creatinine and urea, increases in kidney weight and/or microscopic tubular damage were noted at ≥100 mg/kg. In the mouse, overt kidney toxicity was evident at 600 mg/kg. Linagliptin is an inducer of phospholipidosis in the rat. At 600 mg/kg, foam cells in liver, lung, lymph nodes, spleen, thymus and bone marrow were noted. Also in the rat at doses of ≥100 mg/kg, foci of foam cells were noted in the lung and at 60 mg/kg (approximately 400 times human clinical exposure) in the carcinogenicity study, there was an increased incidence of cholesterol cleft granuloma. There were no indications of effects on the immune system at doses up to 100 mg/kg (approximately 800 times human clinical exposure) for 52 weeks in the monkey, at doses up to 300 mg/kg (approximately 1800 times human clinical exposure) for 26 weeks in the rat, or in the mouse at 600 mg/kg (approximately 3300 times human clinical exposure) for 13 weeks. Increased apoptosis in the thymus, spleen and lymph nodes in rats and monkeys occurred at high doses and were attributed to stress and nonspecific toxicity. The NOAEL after 52 weeks dosing was 10 mg/kg/day in the monkey and 30 mg/kg/day in a 26 week study in rats. At these doses, AUC values were 40 times human clinical exposure in the monkey and 66 times in the rat.

Carcinogenicity

A two-year carcinogenicity study was conducted in male and female rats given oral doses of linagliptin of 6, 18, and 60 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 60 mg/kg/day. This dose results in exposures approximately 400 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 5 mg/day based on AUC comparisons. A two-year carcinogenicity study was conducted in male and female mice given oral doses of 8, 25 and 80 mg/kg/day. There was no evidence of a carcinogenic potential up to 80 mg/kg/day, approximately 240 times human clinical exposure.

Genotoxicity

The mutagenic and clastogenic potential of linagliptin were tested in an in vitro Ames bacterial assay, an in vitro cytogenetics assay in primary human lymphocytes, and an in vivo oral micronucleus assay in rats. Linagliptin was not mutagenic or clastogenic in these studies. The major metabolite was not mutagenic in an in vitro Ames bacterial assay or clastogenic in human lymphocytes.

Reproduction Toxicity

In rat fertility studies with oral gavage doses of 10, 30 and 240 mg/kg/day, males were treated for 4 weeks prior to mating and during mating; females were treated 2 weeks prior to mating through gestation day 6. No adverse effect on early embryonic development, mating, fertility, and bearing live young were observed up to the highest dose of 240 mg/kg/day (approximately 900 times human clinical exposure of 5 mg/day based on AUC comparisons).

In the studies on embryo-fetal development in rats and rabbits, linagliptin was not teratogenic at dosages up to and including 240 mg/kg/day (approximately 900 times human clinical exposure) in the rat and 150 mg/kg/day (approximately 1900 times human clinical exposure) in the rabbit. In the rat, at 240 mg/kg minor maternal toxicity was noted and there was a slight increased resorption rate, slight retardation of skeletal ossification, and also slightly increased incidence of flat and thickened ribs. Administration of 25 and 150 mg/kg to pregnant rabbits resulted in decreased mean body weight gain and decreased food consumption at 150 mg/kg. At 150 mg/kg, linagliptin treatment was associated with intrauterine death, runts (fetuses weighing less than 65% of the weighted control mean values) and an increased incidence of visceral and skeletal variations. A NOAEL of 30 mg/kg/day (approximately 50 times human clinical exposure) and 25 mg/kg/day (approximately 80 times human clinical exposure) was derived for embryo-fetal toxicity in the rat and the rabbit, respectively.

In a pre and postnatal development toxicity study in rats, treatment of the pregnant dams (the F0 generation) at 300 mg/kg (approximately 1500 times human clinical exposure) during gestation and lactation caused decreased maternal body weight gain and food consumption observed during gestation and lactation. The F1 generation of dams treated at 300 mg/kg also showed reduced body weight during lactation and weaning. Their physical postnatal development proceeded in a normal range, except for delayed descensus testis and delayed preputial separation. These effects correlated with reduced body weight and were attributed to general growth retardation. The NOAEL was 30 mg/kg for both maternal and offspring toxicity (approximately 50 times human clinical exposure).