Pharmacokinetics of a Fixed-Dose Combination of Atorvastatin and Metformin Extended Release versus Concurrent Administration of Individual Formulations A Randomized, Open-Label, Two-Treatment, Two-Period, Two-Sequence, Single-Dose, Crossover, Bioequivalence Study

Background: Type 2 diabetes mellitus is associated with a 2- to 4-fold increased risk of coronary heart disease (CHD). Combined therapy with an antihyperglycaemic agent and an HMG-CoA reductase inhibitor (statin) is indicated for the treatment of diabetic patients at risk of CHD. Patients with type 2 diabetes are generally considered to be at equivalent cardiovascular disease risk to patients with established CHD, and should have low-density lipoprotein (LDL) cholesterol levels reduced to <100 mg/dL or by 30-40%. Atorvastatin is the drug of choice for lowering LDL cholesterol levels. Metformin is the first therapeutic option in type 2 diabetes patients who are overweight or obese because it may also prevent vascular complications and mortality. Hence, a fixed-dose combination (FDC) of atorvastatin 10 mg and metformin 500 mg extended release (ER) was developed for patients with type 2 diabetes with or without hyperlipidaemia. Objectives: This study set out to establish bioequivalence between treatment 1 (test) - atorvastatin/metformin ER 10 mg/500 mg FDC, and treatment 2 (reference) - atorvastatin 10 mg (Lipitor (R)) and metformin 500 mg (Glucophage (R) XR) administered concurrently as individual tablets. Methods: The study was a randomized, open-label, two-treatment, two-period, two-sequence, single-dose, crossover, bioequivalence study in 40 male subjects of Asian origin aged 18-45 years. The order of receiving the test and reference treatments for each subject during both the periods of the study wasdetermined according to an SAS (R)-generated randomization schedule. The two treatments were separated by a washout period of 11 days. Blood samples were collected pre-dose and up to 72 hours post-dose in each period for determination of plasma atorvastatin/metformin concentrations and calculation of the respective pharmacokinetic parameters. ANOVA was performed on the lognormal-transformed pharmacokinetic parameters. A 90% confidence interval (CI) for the ratios of the test and reference product averages (least squares means) was calculated for atorvastatin and metformin to establish bioequivalence. Results: The 90% CIs for atorvastatin and metformin were within the bioequivalence acceptance criteria of 80-125%. The 90% CIs obtained for atorvastatin for maximum plasma concentration (C-max), area under the plasma concentration-time curve (AUC) from time zero to time of last measurable concentration (AUC(last)) and AUC from time zero to infinity (AUC(infinity)) were (88.11, 106.93), (91.18, 107.94) and (89.25, 106.60), respectively. The 90% CIs observed for metformin for C-max, AUC(Iast), AUC(infinity) and AUC from time zero to 24 hours (AUC(24)) were (113.3, 124.0), (102.65, 117.97), (101.87, 116.82) and (102.44, 117.53), respectively. The two treatments were well tolerated by the study subjects. Conclusion: Atorvastatin/metformin ER 10 mg/500 mg FDC has similar bioavailability to the co-administration of separate atorvastatin 10 mg and metformin 500 mg tablets. The FDC tablets show similar safety and tolerability profiles to their individual components. Therefore, atorvastatin/metformin ER 10 mg/500 mg FDC tablets can be used safely in clinical settings to decrease the pill burden and increase patient compliance with therapy.