Pharmacokinetics of fixed-dose combination of atorvastatin and metformin compared with individual tablets

Jong-Lyul Ghim,1–3,* Nguyen Thi Thu Phuong,1–2,4,* Min Jung Kim,1,2 Eun-Ji Kim,5 Geun Seog Song,5 Sangzin Ahn,1,2 Jae-Gook Shin,1,2 Eun-Young Kim1–31Department of Pharmacology and Clinical Pharmacology, PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea; 2Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan, Republic of Korea; 3Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea; 4Faculty of Pharmacy, Hai Phong University of Medicine and Pharmacy, Haiphong, Vietnam; 5CJ HealthCare Co., Ltd, Seoul, Republic of Korea*These authors contributed equally to this workPurpose: 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 (Cmax,ss) and area under the plasma concentration–time curve during the dosing interval at steady state (AUCτ,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 (tmax), decreased atorvastatin Cmax by 32% with a GMR (90% CI) of 0.68 (0.59–0.78), and increased metformin AUCt 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.Keywords: pharmacokinetics, drug interaction, atorvastatin, metformin, food effec