title: Pharmacokinetics of a fixed-dose glimepiride/sustained-release metformin combination.
abstract: OBJECTIVE
  Pharmacokinetic (PK) profiles of glimepiride and metformin have been established for the combination drug as well as each agent individually. However, the PK profiles of a combination drug containing glimepiride and sustained-release (SR) metformin have not been reported. To compare the pharmacokinetic profiles of glimepiride/SR metformin (2 mg/500 mg) with the PK of immediate-release (IR) formulations, an open-label, randomized, 3-period, 3-sequence, 3-treatment, crossover study was conducted in 12 healthy subjects.
  
  
  METHODS
  After a single administration of glimepiride/SR metformin 2 mg/500 mg (Treatment) or glimepiride/metformin IR 2 mg/500 mg (Reference 1), or administration of 2 doses of glimepiride/metformin IR 1 mg/250 mg 12 h apart (Reference 2), serial blood samples were collected and drug concentrations determined by liquid chromatography/ tandem mass spectrometry. PK parameters (Cmax and AUC24) for glimepiride and metformin were log-transformed and compared using a mixed-effects model analysis of variance (ANOVA). The mean differences and 95% confidence intervals (CIs) were back-transformed to obtain geometric mean ratios along with the CIs for the ratios.
  
  
  RESULTS
  Treatment demonstrated similar systemic exposures for glimepiride; the geometric mean ratio (95% CIs) for glimepiride AUC24 was 1.05 (0.97 - 1.13) for Treatment relative to Reference 1 and 1.08 (1.00 - 1.17) for Treatment relative to Reference 2. The SR formulation showed a delay in the time to reach maximum concentration for metformin from 1.0 - 4.0 h to 4.0 - 8.0 h and a decreased AUC24 value; the geometric mean ratio for metformin AUC24 was 0.87 (0.74 - 1.03) for Treatment relative to Reference 1 and 0.75 (0.63 - 0.88) for Treatment relative to Reference 2.
  
  
  CONCLUSIONS
  This study demonstrates for the first time that fixed-dose glimepiride and SR metformin 2 mg/500 mg shows a PK profile similar to that of glimepiride, but with a delayed time to maximum concentration and slightly decreased bioavailability for metformin compared with the IR fixed-dose combination, in healthy volunteers. PK profiles from this exploratory study will be helpful in designing and conducting further studies in diabetic patients.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: Kyu-Pyo
authors.initials: KP
authors.lastname: Kim
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Lim
authors.forename: Bo-Hyung
authors.initials: BH
authors.lastname: Kim
authors.forename: Hyun-Suk
authors.initials: HS
authors.lastname: Shin
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001682:Biological Availability; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013607:Tablets; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D003692:Delayed-Action Preparations; D004338:Drug Combinations; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D013607:Tablets; C057619:glimepiride; D008687:Metformin