Bioequivalence of vildagliptin/metformin fixed-dose combination tablets and a free combination of vildagliptin and metformin in healthy subjects.
OBJECTIVE
To assess the bioequivalence of vildagliptin/metformin fixed-dose combination tablets (at doses of 50/500, 50/850 and 50/1,000 mg) with free combination of the individual drugs in healthy subjects.


METHODS
The pharmacokinetics of vildagliptin and metformin following administration of a fixed-dose combination tablet of vildagliptin/metformin at doses of 50/500 mg (Study I), 50/850 mg (Study II) and 50/1,000 mg (Study III) compared with administration of the individual drugs as free combinations were investigated. All three studies were open-label, single-center, randomized, two-period, two-treatment crossover studies in healthy subjects.


RESULTS
Pharmacokinetic parameters (AUC(0-infinity), C(max), t(max), t(1/2) and CL/F) for vildagliptin and metformin across the three studies were similar whether vildagliptin and metformin were administered as a single fixed-dose combination tablet (vildagliptin/metformin 50/500, 50/850 or 50/1,000 mg) or as the respective individual tablets. The point estimates and 90% CI of the geometric mean ratios for vildagliptin and metformin C(max), AUC(0-t), and AUC(0-infinity) were all within the predefined bioequivalence range of 0.80 - 1.25. Administration of the vildagliptin/metformin combination tablets was well tolerated; the incidence of adverse events was similar to that observed with the respective free combinations of vildagliptin and metformin, and the most common individual adverse events were mild gastrointestinal events, which are commonly observed with metformin treatment.


CONCLUSIONS
The fixed-dose combination tablet of vildagliptin/metformin is bioequivalent to administration of the individual drugs as a free combination at dose levels of 50/500, 50/850 and 50/1,000 mg and is well tolerated. Consequently, the fixed-dose combination tablets are considered therapeutically equivalent and exchangeable to the free combination in clinical practice. Furthermore, the fixed-dose combination tablets are expected to enhance convenience and thereby improve compliance and improve glycemic control for patients with Type 2 diabetes on both medications.
Exploratory Developments, Novartis Institutes for Biomedical Research Inc., Cambridge, MA 02139-3584, USA. yanling.he@novartis.com
Y-L
YL
He
S
S
Paladini
H
H
Sabia
J
J
Campestrini
Y
Y
Zhang
S
S
Leon
M
M
Ligueros-Saylan
V
V
Jarugula
D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013607:Tablets; D053719:Tandem Mass Spectrometry; D013810:Therapeutic Equivalency; D000077597:Vildagliptin
D004338:Drug Combinations; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; D013607:Tablets; D008687:Metformin; D000077597:Vildagliptin; D000218:Adamantane