Transl Clin Pharmacol.  2017 Dec;25(4):190-195. 10.12793/tcp.2017.25.4.190.

Pharmacokinetics of atorvastatin and sustained-release metformin fixed-dose combination tablets: two randomized, open-label, 2-way crossover studies in healthy male subjects under fed conditions

• Choi YK
• Park SE
• Kim EY
• Park HJ
• Kim EJ
• Song GS
• Ghim JL

• KMID: 2407001
• DOI: http://doi.org/10.12793/tcp.2017.25.4.190

Abstract

Two separate studies were conducted to establish bioequivalence (BE) for two doses of atorvastatin/metformin sustained-release (SR) fixed dose combination (FDC) versus the same dosage of the individual component (IC) tablets in healthy male subjects under fed conditions (study 1, BE of atorvastatin/metformin SR 20/500 mg FDC; study 2, BE of atorvastatin/metformin SR 20/750 mg FDC). Each study was a randomized, open-label, single oral dose, two-way crossover design. Serial blood samples were collected pre-dose and up to 36 hours post-dose for atorvastatin and 24 hours for metformin. Plasma concentrations of atorvastatin, 2-OH atorvastatin and metformin were analyzed using a validated liquid chromatography tandem mass-spectrometry. A non-compartmental analysis was used to calculate pharmacokinetic (PK) variables and analysis of variance was performed on the lognormal-transformed PK variables. A total of 75 subjects completed the study 1 (36 subjects) and study 2 (39 subjects). The 90% confidence intervals for the adjusted geometric mean ratio of Cmax and the AUC0-t were within the predefined 0.80 to 1.25 range. The number of subjects reporting at least one adverse event following FDC treatments was comparable to that following IC treatments. The two treatments were well tolerated. Therefore, atorvastatin/metformin SR 20/500 mg and 20/750 mg FDC tablets are expected to be used as alternatives to IC tablets to decrease the pill burden and increase patient compliance.

Keyword

Pharmacokinetics; Fixed-dose combination; atorvastatin; metformin extended release

MeSH Terms

Atorvastatin Calcium*
Chromatography, Liquid
Cross-Over Studies*
Humans
Male*
Metformin*
Patient Compliance
Pharmacokinetics*
Plasma
Tablets*
Therapeutic Equivalency
Atorvastatin Calcium
Metformin
Tablets

Figure

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  Figure. 1 Mean (±SD) plasma atorvastatin (a), 2-OH atorvastatin (b) and metformin (c) concentration-time proles 3 after a single oral administration of atorvastatin/metformin 20/500 mg given asthe xed-dose combination tablet 4 or individual component tablets under fed conditions in study 1 (n=36). Dashed horizontal lines show the lower 5 limit of quantication (0.2 ng/mL for both atorvastatin and 2-OH atorvastatin; 10 ng/mL fort metformin). Values 6 below the limit of quantication were entered as 0 and included as such in the calculation of means.

• 

  Figure. 2 Mean (±SD) plasma atorvastatin (a), 2-OH atorvastatin (b) and metformin (c) concentration-time proles after a single oral administration of atorvastatin/metformin 20/750 mg given as xed-dose combination tablet or individual component tablets under fed conditions in study 2 (n=39). Dashed horizontal lines show the lower limit of quantication (0.2 ng/mL for both atorvastatin and 2-OH atorvastatin; 10 ng/mL for metformin).

• 

  Figure. 3 Geometric mean ratios and 90% confidence intervals for atorvastatin and metformin pharmacokinetic variables. Blue circle, study 1 (atorvastatin/metformin 20/500 mg fixed-dose combination (FDC) tablets versus individual component (IC) tablets); red triangle, study 2 (atorvastatin/metformin 20/750 mg FDC tablets versus IC tablets); AUC0–t, area under the concentration-time curve from time 0 to time of the last measurable concentration; Cmax, maximum plasma concentration.

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