Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Blood glucose lowering drugs. Biguanides; ATC code: A10BA02  Mechanism of action
Metformin is a biguanide with antihyperglycaemic effects, on both basal and postprandial hyperglycaemia. It does not stimulate insulin secretion and therefore does not cause hypoglycaemia.

Metformin reduces basal hyperinsulinemia, and in combination with insulin, reduces insulin requirement.
Metformin exerts its antihyperglycaemic effect via multiple mechanisms: Metformin reduces hepatic glucose production.
Metformin facilitates peripheral glucose uptake and utilization, in part by increasing insulin action. Metformin alters glucose turnover in the gut: Uptake from circulation is increased and absorption from food is decreased. Additional mechanisms attributed to the gut include an increase in release of glucagon-like peptide 1 (GLP-1) and a decrease of bile acid resorption.
Metformin alters the gut microbiome.
Metformin can improve the lipid profile in hyperlipidaemic individuals.
In clinical studies, use of metformin was associated with either a stable body weight or modest weight loss.
Metformin is an adenosine monophosphate-protein-kinase (AMPK) activator and increases the transport capacity of all types of membrane glucose transporters (GLUTs).Clinical efficacy
The prospective randomised study (UKPDS) has established the long-term benefit of intensive blood glucose control in adult patients with 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/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034; • a significant reduction of the absolute risk of diabetes-related mortality: metformin 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017;
• a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/1000 patient-years (p=0.021);
• a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01).
Benefit regarding clinical outcome has not been shown for metformin used as second-line therapy, in combination with a sulfonylurea.
In type 1 diabetes, the combination of metformin and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.
Paediatric population
Controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year demonstrated a similar response in glycaemic control to that seen in adults.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
After an oral dose of metformin hydrochloride tablet, maximum plasma concentration (Cmax) is reached in approximately  2.5 hours (tmax). Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60%in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces 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 recommended metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 microgram/ml, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following oral administration of a 850 mg tablet, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of the time to peak plasma concentration were observed. The clinical relevance of these findings 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 volume of distribution (Vd) ranged between 63-276 l.
Metabolism
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 hours.
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.
Characteristics in specific groups of patients
Renal impairment
The available data in subjects with moderate renal insufficiency are scarce and no reliable estimation of the systemic exposure to metformin in this subgroup as compared to subjects with normal renal function could be made. Therefore, the dose adaptation should be made upon clinical efficacy/tolerability considerations (see section 4.2).
Paediatric population
Single dose study: After single doses of metformin hydrochloride 500 mg paediatric patients have shown similar pharmacokinetic profile to that observed in healthy adults.
Multiple dose study: Data are restricted to one study. After repeated doses of 500 mg twice daily for 7 days in paediatric patients the peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively compared to diabetic adults who received repeated doses of 500 mg twice daily for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.