Combining benefits of an adrenergic and a muscarinic blocker in a single formulation - a pharmacokinetic evaluation.

A pharmacokinetic bioequivalence study was conducted in Asian subjects, to compare a fixed dose combination capsule single oral dose of alpha adrenoceptor blocker-Alfuzosin hydrochloride 10mg extended release and muscarinic antagonists-Solifenacin succinate 5mg against individually administered Xatral XL 10mg tablets (Alfuzosin) of Sanofi Synthelabo Limited, United Kingdom (UK) and Vesicare 5mg tablets (Solifenacin) of Astellas Pharma Limited, UK under fed conditions. Blood samples were collected pre-dose up to 72 h post dose for determination of plasma Alfuzosin and Solifenacin concentrations and calculation of the pharmacokinetic parameters. ANOVA was performed on the log (natural)-transformed pharmacokinetic parameters. A 90% confidence interval for the ratios of the test and reference product averages (least square means) were calculated for alfuzosin and solifenacin. The 90% confidence intervals obtained for alfuzosin for Cmax, AUC0-t and AUC0-∞ were 102.74-122.75%, 95.84-116.96% and 95.82-116.76%, respectively. The 90% confidence intervals obtained for Solifenacin for Cmax, and AUC0-72 were 89.55-97.91% and 90.47-99.38%, respectively. Based on the results, the fixed dose combination was concluded to be bioequivalent to individually administered products.

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®) and metformin 500 mg (Glucophage® 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 was determined according to an SAS®-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(∞)) 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(last,) AUC(∞) 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.

Establishing bioequivalence of racemic venlafaxine formulations using stereoselective assay method: Is it necessary?

A bioequivalence study for venlafaxine generic formulation was conducted as an open label, balanced, randomized, two-way crossover, single-dose study. In this study, a comparison of various pharmacokinetic parameters of venlafaxine hydrochloride 150 mg modified release capsules of Ranbaxy and EFEXOR®-XR 150 mg capsules of Wyeth, in healthy, adult, male, human subjects under fasting condition was performed to conclude bioequivalence. Venlafaxine and its major active metabolite O-desmethylvenlafaxine (ODV) are racemates. The "(S)-(+)" and "(R)-(-)" enantiomers of venlafaxine and ODV are established as being active. Hence, subject samples were analyzed using nonstereoselective and stereoselective assay methods. Both (S)-(+) and (R)-(-) enantiomers of venlafaxine and ODV showed similar absorption and disposition. The 90% confidence intervals for venlafaxine, (R)-(-)-venlafaxine as well as (S)-(+)-venlafaxine were within acceptance range concluding bioequivalence. The results obtained by stereoselective assay were comparable to the nonstereoselective analysis, as sum of concentrations of (S)-(+)- and (R)-(-)-enantiomers of venlafaxine and ODV. The mean (S)-(+)/(R)-(-) ratios of the enantiomers of venlafaxine and ODV at various time points were consistent in the study subjects. Therefore, the estimation of venlafaxine and ODV using nonstereoselective assay method is effective in distinguishing formulation differences (if any) in bioequivalence studies in a cost-effective manner.