An Open-Label Drug–Drug Interaction Study of the Steady-State Pharmacokinetics of Topiramate and Glyburide in Patients with Type 2 Diabetes Mellitus

• Published in: Clinical drug investigation Vol. 33; no. 12; pp. 929 - 938
• Main Authors: Manitpisitkul, Prasarn, Curtin, Christopher R., Shalayda, Kevin, Wang, Shean-Sheng, Ford, Lisa, Heald, Donald L.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2013; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Diabetes Mellitus, Type 2 - drug therapy; Drug Interactions; Female; Fructose - administration & dosage; Fructose - analogs & derivatives; Fructose - pharmacokinetics; Fructose - therapeutic use; Glyburide - administration & dosage; Glyburide - pharmacokinetics; Glyburide - therapeutic use; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Middle Aged; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy; Young Adult; Topiramate; Glycemic Control; Glyburide; Fast Plasma Glucose; Systemic Exposure
• ISSN: 1173-2563; 1179-1918
• DOI: 10.1007/s40261-013-0143-4

Background Topiramate is approved for epilepsy and migraine headache management and has potential antidiabetic activity. Because topiramate and antidiabetic drugs may be co-administered, the potential drug–drug interactions between topiramate and glyburide (glibenclamide), a commonly used sulfonylurea antidiabetic agent, was evaluated at steady state in patients with type 2 diabetes mellitus (T2DM). Methods This was a single-center, open-label, phase I, drug interaction study of topiramate (150 mg/day) and glyburide (5 mg/day alone and concomitantly) in patients with T2DM. The study consisted of 14-day screening, 48-day open-label treatment, and a 7-day follow-up phase. Serial blood and urine were obtained and analyzed by liquid chromatography coupled mass spectrometry/mass spectrometry for topiramate, glyburide, and its active metabolites M1 (4- trans -hydroxy-glyburide) and M2 (3- cis -hydroxy-glyburide) concentrations. Pharmacokinetic parameters were estimated by model-independent methods. Changes in fasting plasma glucose from baseline and safety parameters were monitored throughout the study. Results Of 28 enrolled patients, 24 completed the study. Co-administration of topiramate resulted in a significant ( p  < 0.05) decrease in the glyburide area under the concentration–time curve (25 %) and maximum plasma concentration (22 %), and reduction in systemic exposure of M1 (13 %) and M2 (15 %). Renal clearance of M1 (13 %) and M2 (12 %) increased during treatment with topiramate. Steady-state pharmacokinetics of topiramate were unaffected by co-administration of glyburide. Co-administration of topiramate and glyburide was generally tolerable in patients with T2DM. Conclusion Glyburide did not affect the pharmacokinetics of topiramate. Co-administration of topiramate decreased systemic exposure of glyburide and its active metabolites; combined treatment may require dosing adjustments of glyburide as per clinical judgment and glycemic control.