AVANDAMET combines two antihyperglycaemic agents with complimentary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: rosiglitazone maleate, a member of the thiazolidinedione class and metformin hydrochloride, a member of the biguanide class. Thiazolidinediones act primarily by reducing insulin resistance and biguanides act primarily by decreasing endogenous hepatic glucose production.
Rosiglitazone is a selective agonist at the PPARγ (peroxisome proliferator activated receptor gamma) nuclear receptor and is a member of the thiazolidinedione class of antihyperglycaemic agents. It reduces glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver.
The antihyperglycaemic activity of rosiglitazone has been demonstrated in a number of animal models of type 2 diabetes. In addition, rosiglitazone preserved β-cell function as shown by increased pancreatic islet mass and insulin content and prevented the development of overt hyperglycaemia in animal models of type 2 diabetes. Rosiglitazone did not stimulate pancreatic insulin secretion or induce hypoglycaemia in rats and mice. The major metabolite (a para-hydroxy-sulphate) with high affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in obese mice. The clinical relevance of this observation has not been fully elucidated.
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via three mechanisms:
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 glycaemia, 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.
No statistically significant difference was observed between the absorption characteristics of rosiglitazone and metformin from the rosiglitazone/metformin tablet and those obtained from rosiglitazone maleate and metformin hydrochloride tablets, respectively.
Food had no effect on the AUC of rosiglitazone or metformin when rosiglitazone/metformin was administered to healthy volunteers. In the fed state, Cmax was lower (22% rosiglitazone and 15% metformin) and tmax delayed (by approximately 1.5 h rosiglitazone and 0.5 h metformin). This food-effect is not considered clinically significant.
The following statements reflect the pharmacokinetic properties of the individual active substances of rosiglitazone/metformin.
Absolute bioavailability of rosiglitazone following both a 4 and an 8 mg oral dose is approximately 99%. Rosiglitazone plasma concentrations peak at around 1 h after dosing. Plasma concentrations are approximately dose proportional over the therapeutic dose range. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), although a small decrease in Cmax (approximately 20-28%) and a delay in tmax (approximately 1.75 h) were observed compared to dosing in the fasting state. These small changes are not clinically significant and, therefore, it is not necessary to administer rosiglitazone at any particular time in relation to meals. The absorption of rosiglitazone is not affected by increases in gastric pH.
The volume of distribution of rosiglitazone is approximately 14 l in healthy volunteers. Plasma protein binding of rosiglitazone is high (approximately 99.8%) and is not influenced by concentration or age. The protein binding of the major metabolite (a para-hydroxy-sulphate) is very high (>99.99%).
Metabolism of rosiglitazone is extensive with no parent compound being excreted unchanged. The major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with sulphate and glucuronic acid. The contribution of the major metabolite (a para-hydroxy-sulphate) to the overall antihyperglycaemic activity of rosiglitazone has not been fully elucidated in man and it cannot be ruled out that the metabolite may contribute to the activity. However, this raises no safety concern regarding target or special populations as hepatic impairment is contraindicated and the phase III clinical studies included a considerable number of elderly patients and patients with mild to moderate renal impairment.
In vitro studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor contribution by CYP2C9.
Since there is no significant in vitro inhibition of CYP1A2, 2A6, 2C19, 2D6, 2E1, 3A or 4A with rosiglitazone, there is a low probability of significant metabolism-based interactions with substances metabolised by these P450 enzymes. Rosiglitazone showed moderate inhibition of CYP2C8 (IC50 18 µM) and low inhibition of CYP2C9 (IC50 50 µM) in vitro. An in vivo interaction study with warfarin indicated that rosiglitazone does not interact with CYP2C9 substrates in vivo.
Total plasma clearance of rosiglitazone is around 3 l/h and the terminal elimination half-life of rosiglitazone is approximately 3-4 h. There is no evidence for unexpected accumulation of rosiglitazone after once or twice daily dosing. The major route of excretion is the urine with approximately two-thirds of the dose being eliminated by this route, whereas faecal elimination accounts for approximately 25% of dose. No intact active substance is excreted in urine or faeces. The terminal half-life for radioactivity was about 130 h indicating that elimination of metabolites is very slow. Accumulation of the metabolites in plasma is expected upon repeated dosing, especially that of the major metabolite (a para-hydroxy-sulphate) for which an 8-fold accumulation is anticipated.
In the pooled population pharmacokinetic analysis, there were no marked differences in the pharmacokinetics of rosiglitazone between males and females.
In the pooled population pharmacokinetic analysis, age was not found to influence the pharmacokinetics of rosiglitazone to any significant extent.
Population pharmacokinetic analysis including 96 paediatric patients aged 10 to 18 years and weighing 35 to 178 kg suggested similar mean CL/F in children and adults. Individual CL/F in the paediatric population was in the same range as individual adult data. CL/F seemed to be independent of age, but increased with weight in the paediatric population.
In cirrhotic patients with moderate (Child-Pugh B) hepatic impairment, unbound Cmax and AUC were 2- and 3-fold higher than in normal subjects. The inter-subject variability was large, with a 7-fold difference in unbound AUC between patients.
There are no clinically significant differences in the pharmacokinetics of rosiglitazone in patients with renal impairment or end stage renal disease on chronic dialysis.
After an oral dose of metformin, tmax 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 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 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 (Cmax) did not exceed 4 µg/ml, even at maximum doses.
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.
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 Vd ranged between 63-276 l.
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
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.
No animal studies have been conducted with rosiglitazone/metformin. The following data are findings in studies performed with rosiglitazone or metformin individually.
Undesirable effects observed in animal studies with possible relevance to clinical use were as follows: An increase in plasma volume accompanied by decrease in red cell parameters and increase in heart weight. Increases in liver weight, plasma ALT (dog only) and fat tissue were also observed. Similar effects have been seen with other thiazolidinediones.
In reproductive toxicity studies, administration of rosiglitazone to rats during mid-late gestation was associated with foetal death and retarded foetal development. In addition, rosiglitazone inhibited ovarian oestradiol and progesterone synthesis and lowered plasma levels of these hormones resulting in effects on oestrus/menstrual cycles and fertility.
In an animal model for familial adenomatous polyposis (FAP), treatment with rosiglitazone at 200 times the pharmacologically active dose increased tumour multiplicity in the colon. The relevance of this finding is unknown. However, rosiglitazone promoted differentiation and reversal of mutagenic changes in human colon cancer cells in vitro. In addition, rosiglitazone was not genotoxic in a battery of in vivo and in vitro genotoxicity studies and there was no evidence of colon tumours in lifetime studies of rosiglitazone in two rodent species.
Non-clinical 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.
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