t compared to baseline has been observed in all BYDUREON studies. This reduction in body weight was seen in patients treated with BYDUREON 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).
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 BYDUREON resulted in significant reductions in fasting plasma/serum glucose concentrations, these reductions were observed as early as 4 weeks. 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 BYDUREON have indicated improved betacell function, using measures such as the homeostasis model assessments (HOMAB). The durability of effect on beta-cell function was maintained through 52 weeks.
Blood pressure
A reduction in systolic blood pressure was observed in BYDUREON studies (2.9 mmHg to 4.7 mmHg). In the 30 week exenatide twice daily comparator study both BYDUREON and exenatide twice daily significantly reduced systolic blood pressure from base line (4.7±1.1mmHg and 3.4±1.1mmHg respectively) the difference between the treatments was not significant. Improvements in blood pressure were maintained through 52 weeks.
Fasting lipids
BYDUREON has shown no adverse effects on lipid parameters.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with BYDUREON in one or more subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
The absorption properties of exenatide reflect the extended release properties of the BYDUREON 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 BYDUREON, 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.
