Evaluation of pharmacokinetic and pharmacodynamic interaction between the dipeptidyl peptidase IV inhibitor vildagliptin, glyburide and pioglitazone in patients with Type 2 diabetes.
BACKGROUND
Vildagliptin is a selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control and pancreatic b-cell function in patients with Type 2 diabetes. Vildagliptin may be an appropriate agent to combine with other antihyperglycemic agents in patients requiring combination therapy to achieve optimal glycemic control. Two studies were performed to determine the potential for pharmacokinetic and pharmacodynamic interactions between vildagliptin and the sulfonylurea, glyburide, or pioglitazone in patients with Type 2 diabetes.


METHODS
Two open-label, multiple-dose, 3-period, randomized, crossover studies in patients with Type 2 diabetes were carried out. Steady state drug pharmacokinetics and postprandial plasma glucose and insulin responses were assessed during treatment with vildagliptin 100 mg b.i.d. alone and in combination with glyburide 10 mg q.d. (n = 17) or with vildagliptin 100 mg q.d. alone or in combination with pioglitazone 45 mg q.d. (n = 15).


RESULTS
Coadministration of vildagliptin with either glyburide or pioglitazone had no clinically significant effect on the pharmacokinetics of any of the 3 drugs. Changes in AUC and Cmax during combination treatment were small ( pound 15%), and 90% confidence intervals for the geometric mean ratios (drug coadministration/monotherapy) were generally contained within the acceptance range for bioequivalence (0.80 - 1.25). Vildagliptin/glyburide coadministration significantly reduced the area under the plasma glucose-time curve compared with glyburide alone (AUE0-5h reduced by 12% (p = 0.005) and AUE0-15h by 13% (p = 0.003)), and increased the area under the plasma insulin-time curve (AUE0-15h increased by 12% (p = 0.041)). Vildagliptin/pioglitazone coadministration also significantly reduced postprandial glucose exposure compared with pioglitazone alone (AUE0.5-5.5h reduced by 11% (p = 0.029) and AUE0-15.5h by 10% (p = 0.019)). Vildagliptin was generally well tolerated whether administered alone or in combination with glyburide or pioglitazone, and was not associated with hypoglycemia.


CONCLUSIONS
Coadministration of vildagliptin with either glyburide or pioglitazone in patients with Type 2 diabetes improves postprandial glycemic control without notable effects on drug pharmacokinetics.
Serra
D
D
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
He
Y-L
YL
Bullock
J
J
Riviere
G-J
GJ
Balez
S
S
Schwartz
S
S
Wang
Y
Y
Ligueros-Saylan
M
M
Jarugula
V
V
Dole
W P
WP
D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D005905:Glyburide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007328:Insulin / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077205:Pioglitazone; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077597:Vildagliptin
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D009570:Nitriles; D011759:Pyrrolidines; D045162:Thiazolidinediones; D000077597:Vildagliptin; D000218:Adamantane; D005905:Glyburide; D000077205:Pioglitazone