title: An open-label drug-drug interaction study of the steady-state pharmacokinetics of topiramate and glyburide in patients with type 2 diabetes mellitus.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinical Pharmacology, Janssen Research & Development, LLC, 920 Route 202, P.O. Box. 300, Raritan, NJ, USA, PManitpi@its.jnj.com.
authors.forename: Prasarn
authors.initials: P
authors.lastname: Manitpisitkul
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Curtin
authors.forename: Kevin
authors.initials: K
authors.lastname: Shalayda
authors.forename: Shean-Sheng
authors.initials: SS
authors.lastname: Wang
authors.forename: Lisa
authors.initials: L
authors.lastname: Ford
authors.forename: Donald L
authors.initials: DL
authors.lastname: Heald
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004347:Drug Interactions; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005905:Glyburide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077236:Topiramate; D055815:Young Adult
chemical_list: D000077236:Topiramate; D005632:Fructose; D005905:Glyburide