Population pharmacokinetic modeling and noncompartmental analysis demonstrated bioequivalence between metformin component of metformin/vildagliptin fixed-dose combination products and metformin immediate-release tablet sourced from various countries.
Metformin is the first-line pharmacotherapy choice for treating type-2 diabetes mellitus, alone or in combination with other antidiabetic drugs. During the development of immediate-release (IR) metformin containing novel fixed-dose combination (FDC) products, several health-authorities require sponsors to demonstrate bioequivalence between FDC products and the country-sourced metformin for market approval. Eight bioequivalence studies that compared metformin/vildagliptin FDC product (test) to metformin IR tablet sourced from various countries (reference) were conducted. A population pharmacokinetic (PPK) analysis of pooled metformin concentration-time data was performed to evaluate whether country-sourced metformin is a significant covariate. The PPK analysis demonstrated that there was no clinically relevant effect of metformin source or race/ethnicity on metformin pharmacokinetics. Also, noncompartmental analysis conducted showed that 90%CI of geometric mean ratios of test to reference metformin formulations, calculated for maximum-concentration and exposure parameters, were within the 80%-125% criteria, indicating comparable metformin exposure regardless of the country-sourced metformin IR formulation. These results are consistent with the biopharmaceutics properties of metformin and provide scientific evidence that after assessing in vitro dissolution of novel FDC formulation, additional bioequivalence studies with multiple countries' reference products may not be required once bioequivalence is established with 1 country-sourced IR metformin formulation.
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Shripad D
SD
Chitnis
Novartis Institutes for BioMedical Research, Shanghai, China.
Yi
Y
Han
Novartis Pharma K.K., Tokyo, Japan.
Masayuki
M
Yamaguchi
Novartis Pharma K.K., Tokyo, Japan.
Sachiko
S
Mita
Novartis Institutes for BioMedical Research, Shanghai, China.
Rong
R
Zhao
Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
Gangadhar
G
Sunkara
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Kenneth
K
Kulmatycki
D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives; D000293:Adolescent; D000328:Adult; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008875:Middle Aged; D008954:Models, Biological; D009570:Nitriles / Q000008:administration & dosage; D011759:Pyrrolidines / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D013607:Tablets; D013810:Therapeutic Equivalency; D000077597:Vildagliptin; D055815:Young Adult
D004338:Drug Combinations; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; D013607:Tablets; D008687:Metformin; D000077597:Vildagliptin; D000218:Adamantane
bioequivalence; fixed‐dose combination products; metformin; population pharmacokinetics