Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, Glucagon-like peptide-1 (GLP-1) analogues, ATC code: A10BJ01

Mechanism of action
Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist that exhibits several antihyperglycaemic actions of glucagon-like peptide-1 (GLP-1). The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind to and activate the known human GLP-1 receptor in vitro, its mechanism of action mediated by cyclic AMP and/or other intracellular signalling pathways.

Exenatide increases, on a glucose-dependent basis, the secretion of insulin from pancreatic beta cells. As blood glucose concentrations decrease, insulin secretion subsides. When exenatide was used in combination with metformin and/or a thiazolidinedione, no increase in the incidence of hypoglycaemia was observed over that of placebo in combination with metformin and/or a thiazolidinedione which may be due to this glucose-dependent insulinotropic mechanism (see section 4.4).

Exenatide suppresses glucagon secretion which is known to be inappropriately elevated in patients with type 2 diabetes. Lower glucagon concentrations lead to decreased hepatic glucose output. However, exenatide does not impair the normal glucagon response and other hormone responses to hypoglycaemia.

Exenatide slows gastric emptying thereby reducing the rate at which meal-derived glucose appears in the circulation.

Administration of exenatide has been shown to reduce food intake, due to decreased appetite and increased satiety.

Pharmacodynamic effects
Exenatide improves glycaemic control through the sustained effects of lowering both postprandial and fasting glucose concentrations in patients with type 2 diabetes. Unlike native GLP-1, BYDUREON has a pharmacokinetic and pharmacodynamic profile in humans suitable for once weekly administration.

A pharmacodynamic study with exenatide demonstrated in patients with type 2 diabetes (n=13) a restoration of first phase insulin secretion and improved second phase insulin secretion in response to an intravenous bolus of glucose.
Clinical efficacy and safety
The results of long-term clinical studies of BYDUREON are presented below, these studies comprised 1356 subjects treated with BYDUREON, 52% men and 48 % women, 230 subjects (17%) were ≥ 65 years of age.

Glycaemic control
In two studies prolonged-reease exenatideBYDUREON 2 mg once weekly has been compared to exenatide twice daily 5 µg given twice daily for 4 weeks followed by immediate-release exenatide 10 µg given twice daily. One study was of 24 weeks in duration (n= 252) and the other of 30 weeks (n= 295) followed by an open labelled extension where all patients were treated with BYDUREON 2 mg once weekly for a further 7 years (n= 258). In both studies, decreases in HbA1c were evident in both treatment groups as early as the first post-treatment HbA1c measurement (weeks 4 or 6).

Prolonged-release exenatide resulted in a statistically significant reduction in HbA1c compared to patients receiving immediate-release exenatide (Table 2).

A clinically relevant effect of prolonged-release exenatide and immediate-release exenatidetreated subjects was observed on HbA1c, regardless of the background anti-diabetic therapy in both studies.

Clinically and statistically significantly more subjects on prolonged-release compared to immediate- release exenatidepatients achieved an HbA1c reduction of ≤ 7 % or < 7 % in the two studies (p < 0.05 and p=< 0.0001 respectively).

Both prolonged-release and immediate-release exenatide patients achieved a reduction in weight compared to baseline, although the difference between the two treatment arms was not significant.

In the uncontrolled study extension, evaluable patients who switched from immediate-release to prolonged-release exenatide at week 30 (n=121), achieved the same improvement in HbA1c of -2.0% at week 52 compared to baseline as patients treated with prolonged-release exenatide. For all patients completing the uncontrolled study extension of 7 years (n=122 of 258 patients included in the extension phase), HbA1c gradually increased over time from week 52 onwards, but was still reduced compared to baseline after 7 years (-1.1%). Weight loss was sustained over 7 years in these patients.
Table2: Results of two trials of prolonged-release versus immediate-release exenatide in combination with diet and exercise alone, metformin and/or sulphonylurea and metformin and/or thiazolidinedione (intent to treat patients).

24 Week Study                                                          BYDUREON          Exenatide 10 µg
2 mg              twice daily
N                                                                           129                  123 Mean HbA1c (%)
Baseline                                                                     8.5                   8.4 Change from baseline (± SE)                                            -1.6 (±0.1) **          -0.9 (±0.1) Mean difference change from baseline between treatments                        -0.67 (-0.94, -0.39) ** (95 % CI)
Patients (%) achieving HbA1c < 7 %                                          58                    30 Change in fasting plasma glucose (mmol/l) (± SE)                        -1.4 (±0.2)           -0.3 (±0.2) Mean body weight (kg)
Baseline                                                                    97                    94 Change from baseline (± SE)                                             -2.3 (±0.4)          -1.4 (± 0.4) Mean difference change from baseline between treatments                         -0.95 (-1.91, 0.01) (95 % CI)
30 Week Study
N                                                                           148                   147 Mean HbA1c (%)
Baseline                                                                    8.3                  8.3 Change from baseline (± SE)                                            -1.9 (±0.1) *         -1.5 (±0.1) Mean difference change from baseline between treatments                       -0.33 (-0.54, -0.12) * (95 % CI)
Patients (%) achieving HbA1c ≤ 7 %                                          73                    57 Change in fasting plasma glucose (mmol/l) (± SE)                        -2.3 (±0.2)           -1.4 (±0.2) Mean body weight (kg)
Baseline                                                                    102                  102 Change from baseline (± SE)                                             -3.7 (±0.5)          -3.6 (±0.5) Mean difference change from baseline between treatments                         -0.08 (-1.29, 1.12) (95 % CI)
SE = standard error, CI= confidence interval), * p< 0.05, **p< 0.0001 A study of 26-week duration has been conducted, in which prolonged-release exenatide 2 mg is compared to insulin glargine once daily. prolonged-release exenatide demonstrated a superior change in HbA1c compared to insulin glargine. Compared with insulin glargine treatment, prolonged-release exenatide treatment significantly lowered mean body weight and was associated with fewer hypoglycaemic events (Table 3).
Table 3: Results of one 26-week trial of prolonged-release exenatide versus insulin glargine in combination with metformin and/or sulphonylurea (intent to treat patients).

BYDUREON                   Insulin
1
2 mg                       Glargine
N                                                                                   233                       223 Mean HbA1c (%)
Baseline                                                                               8.3                8.3 Change from baseline (± SE)                                                      -1.5 (± 0.1) *     -1.3 (± 0.1) * Mean difference change from baseline between                                         -0.16 (-0.29, -0.03) * treatments (95 % CI)
Patients (%) achieving HbA1c ≤ 7 %                                                      62                      54 Change in fasting serum glucose (mmol/l) (± SE)                                    -2.1 (± 0.2)            -2.8 (± 0.2) Mean body weight (kg)
Baseline                                                                                91                91 Change from baseline (± SE)                                                        -2.6 (± 0.2)      +1.4 (±0.2) Mean difference change from baseline between                                          -4.05 (-4.57, -3.52) * treatments (95 % CI)
SE = standard error, CI= confidence interval), * p<0.05, **p<0.0001
1
Insulin glargine was dosed to a target glucose concentration of 4.0 to 5.5 mmol/l (72 to 100 mg/dl). The mean dose of insulin glargine at the beginning of treatment was 10.1 IU/day rising to 31.1 IU/day for insulin glargine-treated patients.

The 156-week results were consistent with those previously reported in the 26-week interim report.
Treatment with prolonged-release exenatide persistently significantly improved glycaemic control and weight control compared to the insulin glargine treatment. Safety findings at 156 weeks were consistent with those reported at 26 weeks.

In a 26-week double blind study prolonged-release exenatide was compared to maximum daily doses of sitagliptin and pioglitazone in subjects also using metformin. All treatment groups had a significant reduction in HbA1c compared to baseline. prolonged-release exenatide demonstrated superiority to both sitagliptin and pioglitazone with respect to change in HbA1c from baseline.
 prolonged-release exenatide demonstrated significantly greater weight reductions compared to sitagliptin. Patients on pioglitazone gained weight (Table 4).
Table 4: Results of one 26-week trial of prolonged-release exenatide versus sitagliptin and versus pioglitazone in combination with metformin (intent to treat patients).
BYDUREON              Sitagliptin         Pioglitazone
2 mg               100 mg                45 mg
N                                                    160                 166                  165 Mean HbA1c (%)
Baseline                                             8.6                 8.5                  8.5 Change from baseline (± SE)                    - -1.6(± 0.1) *      -0.9 (± 0.1) *       -1.2(± 0.1) * Mean difference change from baseline                           -0.63 (, -0.89, -0.37) ** between treatments (95 % CI) versus sitagliptin
Mean difference change from baseline                             -0.32 (-0.57, -0.06,)* between treatments (95 % CI) versus pioglitazone
Patients (%) achieving HbA1c ≤ 7 %                    62                  36                   49 Change in fasting serum glucose                  -1.8 (± 0.2)        -0.9 (± 0.2)         -1.5 (± 0.2) (mmol/l) (± SE)
Mean body weight (kg)
Baseline                                              89                  87                   88 Change from baseline (± SE)                      -2.3 (± 0.3)        -0.8 (± 0.3)        +2.8 (± 0.3) Mean difference change from baseline                             -1.54 (-2.35, -0.72) * between treatments (95 % CI) versus sitagliptin
Mean difference change from baseline                            -5.10 (-5.91, -4.28) ** between treatments (95 % CI) versus pioglitazone
SE = standard error, CI= confidence interval), * p< 0.05, **p< 0.0001 
In a 28-week, double-blind study, the combination of prolonged-release exenatide and dapagliflozin was compared to prolonged-release exenatide alone and dapagliflozin alone in subjects also using metformin. All treatment groups had a reduction in HbA1c compared to baseline. The prolonged-release exenatide and dapagliflozin treatment group showed superior reductions in HbA1c from baseline compared to prolonged-release exenatide alone and dapagliflozin alone (Table 5).

The combination of prolonged-release exenatide and dapagliflozin demonstrated significantly greater weight reductions compared to either agent alone (Table 5).

Table 5: Results of one 28-week trial of prolonged-release exenatide and dapagliflozin versus prolonged- release exenatide alone and dapagliflozin alone, in combination with metformin (intent to treat patient) Prolonged-          Prolonged-           Dapagliflozin release             release             10 mg QD exenatide 2       exenatide 2 mg              + mg QW                QW                Placebo QW
+                   +
Dapagliflozin       Placebo QD
10 mg QD
N                                                      228                 227                    230 Mean HbA1c (%)
Baseline                                                9.3                9.3                   9.3 Change from baseline (± SE) a                       - 2 (± 0.1)        -1.6 (± 0.1)          -1.4 (± 0.1) Mean difference in change from baseline
-0.38*               -0.59** between combination and single active
(-0.63, -0.13)        (-0.84, -0.34) agent (95 % CI)
Patients (%) achieving HbA1c < 7 %                      45                  27                    19 Mean change from baseline in fasting
-3.7 (±0.2)          -2.5 (±0.2)           -2.7 (±0.2) plasma glucose (mmol/l) (±SE) a
Mean difference in change from baseline
-1.12**               -0.92** between combination and single active
(-1.55, -0.68)        (-1.36, -0.49) agent (95% CI)
Mean change from baseline in 2-hour postprandial plasma glucose (mmol/L)               -4.9 (±0.2)          -3.3 (±0.2)           -3.4 (±0.2) (±SE) a
Mean difference in change from baseline
-1.54**               -1.49** between combination and single active
(-2.10, -0.98)        (-2.04, -0.93) agent (95 % CI)
Mean body weight (kg)
Baseline                                               92                   89                    91 Change from baseline (± SE) a                      -3.6 (±0.3)          -1.6 (±0.3)           -2.2 (±0.3) Mean difference in change from baseline
-2.00**               -1.33** between combination and single active
(-2.79, -1.20)        (-2.12, -0.55) agent (95 % CI)
QW=once weekly, QD=once daily, SE = standard error, CI= confidence interval, N=number of patients.
a Adjusted least squares means (LS Means) and treatment group difference(s) in the change from baseline values at Week 28 are modelled using a mixed model with repeated measures (MMRM) including treatment, region, baseline HbA1c stratum (< 9.0 % or ≥ 9.0 %), week, and treatment by week interaction as fixed factors, and baseline value as a covariate.
*p < 0.01, **p < 0.001.
P-values are all adjusted p-values for multiplicity.
Analyses exclude measurements post rescue therapy and post premature discontinuation of study medicinal product.

In a 28-week double-blind study, prolonged-release exenatide added to insulin glargine alone or with metformin was compared to placebo added to insulin glargine alone or with metformin. Insulin glargine was dosed targeting a fasting plasma glucose of 4.0 to 5.5 mmol/l (72 to 99 mg/dl). prolonged-release exenatide demonstrated superiority to placebo in reducing HbA1c from baseline to Week 28 (Table 6).
prolonged-release exenatide was superior to placebo in reducing body weight at Week 28 (Table 6).

Table 6: Results of one 28-week trial of prolonged-release exenatide versus placebo in combination with insulin glargine alone or with metformin (intent to treat patients) Prolonged-release
Placebo exenatide 2 mg
+ Insulin glargine a
+ Insulin glargine a
N                                                                 231                               230 Mean HbA1c (%)
Baseline                                                            8.5                             8.5 Change from baseline (± SE) b                                  - 1.0 (± 0.1)                    -0.2 (± 0.1) Mean difference in change from baseline                                            -0.73* between treatments (95% CI)                                                    (-0.93, -0.53) Patients (%) achieving HbA1c ≤7% c                                 33*                               7 Mean body weight (kg)
Baseline                                                            94                              94 Change from baseline (± SE) b                                   -1.0 (±0.3)                     0.5 (±0.3) Mean difference in change from baseline                                            -1.50* between treatments (95% CI)                                                    (-2.17, -0.84) Change from baseline in 2-hour postprandial
-1.6 (±0.3)                     -0.1 (±0.3) plasma glucose (mmol/l) (± SE) b,d
Mean difference in change from baseline                                            -1.52* between treatments (95% CI)                                                    (-2.15, -0.90) N=number of patients in each treatment group, SE = standard error, CI= confidence interval, *p-value <0.001 (adjusted for multiplicity).
a. The LS means change in mean daily insulin dose was 1.6 units for the prolonged-release exenatide group and 3.6 units for the placebo group.
b. Adjusted LS means and treatment group difference(s) in the change from baseline values at Week 28 are modeled using a mixed model with repeated measures (MMRM) including treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), baseline SU-use stratum (yes vs. no), week, and treatment by week interaction as fixed factors, and baseline value as a covariate. The absolute change in 2-hour postprandial plasma glucose at Week 28 is modeled similarly using ANCOVA.
c. All patients with missing endpoint data are imputed as non-responders.
d. After a standard meal tolerance test.
Analyses exclude measurements post rescue therapy and post premature discontinuation of study medication.

Body weight
A reduction in body weight compared to baseline has been observed in all prolonged-release exenatide studies. In the 4 comparator-controlled studies, this reduction in body weight was seen in patients treated with prolonged-release exenatide irrespective of the occurrence of nausea although the reduction was larger in the group with nausea (mean reduction - 2.9 kg to - 5.2 kg with nausea versus - 2.2 kg to -2.9 kg without nausea).

In the 4 comparator-controlled studies, the proportion of patients who had both a reduction in weight and HbA1c ranged from 70 to 79 % (the proportion of patients who had a reduction of HbA1c ranged from 88 to 96 %).

Plasma/serum glucose
Treatment with prolonged-release exenatide resulted in significant reductions in fasting plasma/serum glucose concentrations, these reductions were observed as early as 4 weeks. In the placebo-controlled study with insulin glargine, the change from baseline to Week 28 in fasting plasma glucose was -0.7 mmol/l for the prolonged-release exenatide group and -0.1 mmol/l for the placebo group. Additional reductions in postprandial concentrations were also observed. The improvement in fasting plasma glucose concentrations was durable through 52 weeks.
Beta-cell function
Clinical studies with prolonged-release exenatide have indicated improved beta-cell function, using measures such as the homeostasis model assessments (HOMA-B). The durability of effect on beta-cell function was maintained through 52 weeks.

Blood pressure
A reduction in systolic blood pressure was observed in the 4 comparator-controlled prolonged- release exenatide studies (2.9 mmHg to 4.7 mmHg). In the 30-week immediate-release exenatide comparator study both prolonged-release and immediate-release significantly reduced systolic blood pressure from base line (4.7±1.1 mmHg and 3.4±1.1 mmHg respectively) the difference between the treatments was not significant. Improvements in blood pressure were maintained through 52 weeks.

In the placebo-controlled study with insulin glargine, the change from baseline to Week 28 in systolic blood pressure was -2.6 mmHg for the prolonged-release exenatide group and -0.7 mmHg for the placebo group.

Treatment with prolonged-release exenatide and dapagliflozin combination at Week 28 resulted in a significant mean change reduction of -4.3±0.8 mmHg in systolic blood pressure compared to prolonged- release exenatide alone of -1.2±0.8 mmHg (p<0.01) or to dapagliflozin alone of -1.8±0.8 mmHg (p<0.05).

Fasting lipids prolonged-release exenatide has shown no adverse effects on lipid parameters.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
The absorption properties of exenatide reflect the extended release properties of the prolonged-release exenatide formulation. Once absorbed into the circulation, exenatide is distributed and eliminated according to its known systemic pharmacokinetic properties (as described in this section).

Absorption
Following weekly administration of 2 mg prolonged-release exenatide, mean exenatide concentrations exceeded minimal efficacious concentrations (~ 50 pg/ml) in 2 weeks with gradual increase in the average plasma exenatide concentration over 6 to 7 weeks. Subsequently, exenatide concentrations of approximately 300 pg/ml were maintained indicating that steady-state was achieved. Steady-state exenatide concentrations are maintained during the one-week interval between doses with minimal peak to trough fluctuation from this average therapeutic concentration.

Distribution
The mean apparent volume of distribution of exenatide following subcutaneous administration of a single dose of exenatide is 28 L.

Biotransformation and elimination
Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide is 9 l/h. These pharmacokinetic characteristics of exenatide are independent of the dose. Approximately 10 weeks after discontinuation of BYDUREON therapy, mean plasma exenatide concentrations fell below minimal detectable concentrations.
Special populations
Renal impairment
Population pharmacokinetic analysis of renal impaired patients receiving 2 mg prolonged-release exenatide indicate that there may be an increase in systemic exposure of approximately 74 % and 23 % (median prediction in each group) in moderate (N=10) and mild (N=56) renal impaired patients, respectively as compared to normal (N=84) renal function patients.

Hepatic insufficiency
No pharmacokinetic study has been performed in patients with hepatic insufficiency. Exenatide is cleared primarily by the kidney, therefore hepatic dysfunction is not expected to affect blood concentrations of exenatide.

Gender, race and body weight
Gender, race and body weight have no clinically relevant influence on exenatide pharmacokinetics.

Elderly
Data in elderly are limited but suggest no marked changes in exenatide exposure with increased age up to about 75 years old.

In a pharmacokinetic study of exenatide twice daily in patients with type 2 diabetes, administration of exenatide (10 µg) resulted in a mean increase of exenatide AUC by 36 % in 15 elderly subjects aged 75 to 85 years compared to 15 subjects aged 45 to 65 years likely related to reduced renal function in the older age group (see section 4.2).

Paediatric population
In a single-dose pharmacokinetic study of exenatide twice daily in 13 patients with type 2 diabetes and between the ages of 12 and 16 years, administration of exenatide (5 µg) resulted in slightly lower mean AUC (16 % lower) and Cmax (25 % lower) compared to those observed in adults. No pharmacokinetics study of prolonged-release exenatide has been conducted in the paediatric population.