title: Effect of canagliflozin on the pharmacokinetics of glyburide, metformin, and simvastatin in healthy participants.
abstract: Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor, and glyburide, metformin, and simvastatin were evaluated in three phase-1 studies in healthy participants. In these open-label, fixed sequence studies, participants received: Study 1-glyburide 1.25 mg/day (Day 1), canagliflozin 200 mg/day (Days 4-8), canagliflozin with glyburide (Day 9); Study 2-metformin 2,000 mg/day (Day 1), canagliflozin 300 mg/day (Days 4-7), metformin with canagliflozin (Day 8); Study 3-simvastatin 40 mg/day (Day 1), canagliflozin 300 mg/day (Days 2-6), simvastatin with canagliflozin (Day 7). Pharmacokinetic parameters were assessed at prespecified intervals. Co-administration of canagliflozin and glyburide did not affect the overall exposure (maximum plasma concentration [Cmax ] and area under the plasma concentration-time curve [AUC]) of glyburide and its metabolites (4-trans-hydroxy-glyburide and 3-cis-hydroxy-glyburide). Canagliflozin did not affect the peak concentration of metformin; however, AUC increased by 20%. Though Cmax and AUC were slightly increased for simvastatin (9% and 12%) and simvastatin acid (26% and 18%) following coadministration with canagliflozin, compared with simvastatin administration alone; however, no effect on active 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitory activity was observed. There were no serious adverse events or hypoglycemic episodes. No drug-drug interactions were observed between canagliflozin and glyburide, metformin, or simvastatin. All treatments were well-tolerated in healthy participants.
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Damayanthi
authors.initials: D
authors.lastname: Devineni
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Prasarn
authors.initials: P
authors.lastname: Manitpisitkul
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Murphy
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Skee
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Ewa
authors.initials: E
authors.lastname: Wajs
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Rao N V S
authors.initials: RN
authors.lastname: Mamidi
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Tian
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Vandebosch
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Shean-Sheng
authors.initials: SS
authors.lastname: Wang
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Verhaeghe
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Stieltjes
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Usiskin
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001118:Argentina; D001682:Biological Availability; D001711:Biotransformation; D000068896:Canagliflozin / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005905:Glyburide / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D008954:Models, Biological; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014481:United States; D055815:Young Adult
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D000068896:Canagliflozin; D008687:Metformin; D019821:Simvastatin; D005905:Glyburide
keywords: canagliflozin; glyburide; metformin; pharmacokinetics; simvastatin; type-2 diabetes mellitus