Source: European Medicines Agency (EU) Publisher: SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom
Pharmacotherapeutic group: oral blood glucose lowering drugs, thiazolidinediones
ATC code: A10BG02
Rosiglitazone is a selective agonist at the PPARγ (peroxisomal proliferator activated receptor gamma) nuclear receptor and is a member of the thiazolidinedione class of anti-diabetic 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 ß-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 (para-hydroxy-sulphate) with high affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in obese mouse. The clinical relevance of this observation has not been fully elucidated.
The glucose lowering effects observed with rosiglitazone are gradual in onset with near maximal reductions in fasting plasma glucose (FPG) evident following approximately 8 weeks of therapy. The improved glycaemic control is associated with reductions in both fasting and post-prandial glucose.
Rosiglitazone was associated with increases in weight. In mechanistic studies, the weight increase was predominantly shown to be due to increased subcutaneous fat with decreased visceral and intra-hepatic fat.
Consistent with the mechanism of action, rosiglitazone reduced insulin resistance and improved pancreatic ß-cell function. Improved glycaemic control was also associated with significant decreases in free fatty acids. As a consequence of different but complementary mechanisms of action, dual oral therapy of rosiglitazone with a sulphonylurea or metformin resulted in additive effects on glycaemic control in type 2 diabetic patients.
In studies with a maximal duration of three years, rosiglitazone given once or twice daily produced a sustained improvement in glycaemic control (FPG and HbA1c). A more pronounced glucose-lowering effect was observed in obese patients. An outcome study has not been completed with rosiglitazone, therefore the long-term benefits associated with improved glycaemic control have not been demonstrated.
An active controlled clinical trial (rosiglitazone up to 8 mg daily or metformin up to 2,000 mg daily) of 24 weeks duration was performed in 197 children (10-17 years of age) with type 2 diabetes. Improvement in HbA1c from baseline achieved statistical significance only in the metformin group. Rosiglitazone failed to demonstrate non-inferiority to metformin. Following rosiglitazone treatment, there were no new safety concerns noted in children compared to adult patients with type 2 diabetes mellitus. No long-term efficacy and safety data are available in paediatric patients.
ADOPT (A Diabetes Outcome Progression Trial) was a multicentre, double-blind, controlled trial with a treatment duration of 4-6 years (median duration of 4 years), in which rosiglitazone at doses of 4 to 8 mg/day was compared to metformin (500 mg to 2000 mg/day) and glibenclamide (2.5 to 15 mg/day) in 4351 drug naive subjects recently diagnosed (≤3 years) with type 2 diabetes. Rosiglitazone treatment significantly reduced the risk of reaching monotherapy failure (FPG>10.0 mmol/L) by 63% relative to glibenclamide (HR 0.37, CI 0.30-0.45) and by 32% relative to metformin (HR 0.68, CI 0.55-0.85) during the course of the study (up to 72 months of treatment). This translates to a cumulative incidence of treatment failure of 10.3% for rosiglitazone, 14.8% for metformin and 23.3% for glibenclamide treated patients. Overall, 43%, 47% and 42% of subjects in the rosiglitazone, glibenclamide and metformin groups respectively withdrew due to reasons other than monotherapy failure. The impact of these findings on disease progression or on microvascular or macrovascular outcomes has not been determined (see section 4.8). In this study, the adverse events observed were consistent with the known adverse event profile for each of the treatments, including continuing weight gain with rosiglitazone. An additional observation of an increased incidence of bone fractures was seen in women with rosiglitazone (see sections 4.4 and 4.8).
The RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes) trial was a large (4,447 subjects), open-label, prospective, controlled study (mean follow-up 5.5 years) in which patients with type 2 diabetes inadequately controlled with metformin or sulphonylurea were randomised to add-on rosiglitazone or metformin or sulphonylurea. The mean duration of diabetes in these patients was approximately 7 years. The adjudicated primary endpoint was cardiovascular hospitalisation (which included hospitalisations for heart failure) or cardiovascular death. Mean doses at the end of randomised treatment are shown in the following table:
| Randomised Treatment† | Mean (SD) dose at end of randomised treatment |
|---|---|
| Rosiglitazone (either SU or metformin) | 6.7 (1.9) mg |
| Sulphonylurea (background metformin) | |
| Glimepiride* | 3.6 (1.8) mg |
| Metformin (background sulphonylurea) | 1995.5 (682.6) mg |
* Similar relative effective doses (i.e approximately half maximal dose) for other sulphonylureas (glibenclamide and glicazide).
† Patients who took designated treatment as randomised in combination with the correct background treatment and with evaluable data.
No difference in the number of adjudicated primary endpoint events for rosiglitazone (321/2220) versus active control (323/2227) (HR 0.99, CI 0.85-1.16) was observed, meeting the pre-defined noninferiority criterion of 1.20 (non-inferiority p=0.02). HR and CI for key secondary endpoints were: all-cause death (HR 0.86, CI 0.68-1.08), MACE (Major Adverse Cardiac Events – cardiovascular death, acute myocardial infarction, stroke) (HR 0.93, CI 0.74-1.15), cardiovascular death (HR 0.84, CI 0.59-1.18), acute myocardial infarction (HR 1.14, CI 0.80-1.63) and stroke (HR 0.72, CI 0.49-1.06). In a sub-study at 18 months, add-on rosiglitazone dual therapy was non-inferior to the combination of sulphonylurea plus metformin for lowering HbA1c. In the final analysis at 5 years, an adjusted mean reduction from baseline in HbA1c of 0.14% for patients on rosiglitazone added to metformin versus an increase of 0.17% for patients taking sulphonylurea added to metformin was seen during treatment with randomised dual-combination therapy (p<0.0001 for treatment difference). An adjusted mean reduction in HbA1c of 0.24% was seen for patients taking rosiglitazone added to sulphonylurea, versus a reduction in HbA1c of 0.10% for patients taking metformin added to sulphonylurea, (p=0.0083 for treatment difference). There was a significant increase in heart failure (fatal and nonfatal) (HR 2.10, CI 1.35-3.27) and bone fractures (Risk Ratio 1.57, CI 1.26-1.97) in rosiglitazonecontaining treatments compared to active control (see sections 4.4 and 4.8). A total of 564 patients withdrew from cardiovascular follow-up, which accounted for 12.3% of rosiglitazone patients and 13% of control patients; representing 7.2% of patient-years lost for cardiovascular events follow-up and 2.0% of patient-years lost for all cause mortality follow-up.
Absolute bioavailability of rosiglitazone following both a 4 and an 8 mg oral dose is approximately 99%. Rosiglitazone plasma concentrations peak at around 1 hour 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% to 28%) and a delay in tmax (ca.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 litres 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 (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 (para-hydroxy-sulphate) to the overall anti-diabetic 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 (see section 4.5). 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 to 4 hours. 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 drug is excreted in urine or faeces. The terminal half-life for radioactivity was about 130 hours 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 (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.
Adverse 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 (see section 4.4).
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.
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