<p>Pharmacokinetics of fixed-dose combination of atorvastatin and metformin compared with individual tablets</p>

Abstract

Purpose: The aims of this study was to investigate the mutual pharmacokinetic interactions between steady-state atorvastatin and metformin and the effect of food on the fixed-dose combined (FDC) tablet of atorvastatin and metformin extended release (XR). Subjects and methods: Study 1, an open-labeled, fixed sequence, multiple-dose pharmacokinetic drug-drug interaction study, was divided into 2 parts. Atorvastatin (40 mg) or metformin (1,000 mg) XR tablets were administered once daily via mono- or co-therapy for 7 days. Plasma levels of atorvastatin and 2-OH-atorvastatin, were quantitatively determined for 36 h in part A (n=50) while metformin plasma concentration was measured up to 24 h in part B (n=16) after the last dosing. Study 2, a randomized, open-labeled, single-dose, two-treatment, two-period, two-sequence crossover study, involved 27 healthy subjects to investigate the impact of food intake on the pharmacokinetics of a combined atorvastatin/metformin XR 20/500 mg (CJ-30056 20/500 mg) tablet. Results: After multiple doses of mono- or co-therapy of atorvastatin (40 mg) and metformin (1,000 mg) XR, the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for the peak plasma concentration at steady state (C max,ss ) and area under the plasma concentration–time curve during the dosing interval at steady state (AUC τ,ss ) were 1.07 (0.94–1.22) and 1.05 (0.99–1.10) for atorvastatin, 1.06 (0.96–1.16) and 1.16 (1.10–1.21) for 2-OH-atorvastatin, and 1.00 (0.86–1.18) and 0.99 (0.87–1.13) for metformin, respectively. Food delayed time to reach maximum concentration (t max ), decreased atorvastatin C max by 32% with a GMR (90% CI) of 0.68 (0.59–0.78), and increased metformin AUC t by 56% with a GMR (90% CI) of 1.56 (1.43–1.69). Conclusion: No clinically relevant pharmacokinetic interaction was seen when atorvastatin was co-administered with metformin. Food appeared to change the absorption of atorvastatin and metformin from an FDC formulation. These alterations were in accordance with those described with the single reference drugs when ingested with food.

A pharmacokinetics‐based approach to the monitoring of patient adherence to atorvastatin therapy

“…Based on the equation t 1 /2 = ln2/K e , our estimates of the median systemic half‐lives (t 1/2 ) of ATR+ATRL and ATR+MET are 5.1 h and 6.3 h, respectively. These values are lower than that cited in the regulatory documents of ATR formulations (14 h), but are similar to those reported by others 31‐34 . Lins et al established mean half‐lives of 11.5 and 10.9 h for ATR after administering high doses (40 mg or 80 mg, respectively) 35 .…”

“…These values are lower than that cited in the regulatory documents of ATR formulations (14 h), but are similar to those reported by others. 31 , 32 , 33 , 34 Lins et al established mean half‐lives of 11.5 and 10.9 h for ATR after administering high doses (40 mg or 80 mg, respectively). 35 The proposed reasons for these differences are the evaluation of ATR+ATRL and ATR+MET, the use of a single‐compartment model, and heavily relying on early sample collection.…”

Effects of Statin Combinations on Zika Virus Infection in Vero Cells

“…Our previous study and this study suggest that the potency of statins as lipid-lowering agents was not translatable to their effectivity against the ZIKV in vitro, as FLU was consistently the most potent statin based on the concentration that reached the maximum inhibition of ZIKV production and infectivity in Vero cells ( Table 5 ). The EC 50 values obtained in this study were in micromolar concentrations and were much higher than the nanomolar peak (C max ) and the steady-state serum concentrations (C ss ) achievable for current ATO and SIM dosing [ 31 , 32 , 33 ]. However, the micromolar concentrations of FLU in the serum may be achievable in the immediate-release formulation of fluvastatin (fluvastatin IR) [ 34 ].…”

In Vitro Dissolution and In Vivo Bioequivalence Evaluation of Two Metformin Extended‐Release Tablets

“…As a substrate of organic cation transporters, the pharmacokinetics of metformin can be altered by inhibitors of organic cation transporters such as cimetidine and trimethoprim that contribute to variability of drug responses 5 . Food can affect the absorption and pharmacokinetic profile of metformin; however, these changes do not appear to be clinically meaningful 6‐10 . Furthermore, because of its common gastrointestinal side effects, it is recommended that metformin should be taken with meals to reduce gastrointestinal symptoms 11,12 …”