title: Effects of hydrochlorothiazide on the pharmacokinetics, pharmacodynamics, and tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants.
abstract: BACKGROUND
  Many patients with type 2 diabetes mellitus (T2DM) also have hypertension, which is commonly treated with thiazide diuretics, including hydrochlorothiazide (HCTZ). Canagliflozin, a sodium glucose cotransporter 2 inhibitor developed for the treatment of T2DM, lowers plasma glucose by inhibiting renal glucose reabsorption, thereby increasing urinary glucose excretion and mild osmotic diuresis. Because patients with T2DM are likely to receive concurrent canagliflozin and HCTZ, potential interactions were evaluated.
  
  
  OBJECTIVE
  This study evaluated the effects of HCTZ on the pharmacokinetic and pharmacodynamic properties and tolerability of canagliflozin in healthy participants.
  
  
  METHODS
  This Phase I, single-center, open-label, fixed-sequence, 2-period study was conducted in healthy participants. During period 1, participants received canagliflozin 300 mg once daily for 7 days, followed by a 14-day washout period. During period 2, participants received HCTZ 25 mg once daily for 28 days, followed by canagliflozin 300 mg + HCTZ 25 mg once daily for 7 days. Blood samples were taken before and several times after administration on day 7 of period 1 and on days 28 and 35 of period 2 for canagliflozin and HCTZ pharmacokinetic analyses using LC-MS/MS. Blood and urine samples were collected for up to 24 hours after canagliflozin administration on day 1 of period 1 and day 35 of period 2 for pharmacodynamic glucose assessment. Tolerability was also evaluated.
  
  
  RESULTS
  Thirty participants were enrolled (16 men, 14 women; all white; mean age, 43.7 years). Canagliflozin AUC during a dosing interval (T) at steady state (AUCτ,ss) and Cmax at steady state (Cmax,ss) were increased when canagliflozin was coadministered with HCTZ, with geometric mean ratios (90% CI) of 1.12 (1.08-1.17) and 1.15 (1.06-1.25), respectively. AUCτ,ss and Cmax,ss for HCTZ were similar with and without canagliflozin coadministration. The 24-hour mean renal threshold for glucose and mean plasma glucose were comparable for canagliflozin alone and coadministered with HCTZ. The change in 24-hour urine volume from baseline was -0.1 L with canagliflozin alone and 0.4 L with HCTZ alone and with canagliflozin + HCTZ. The overall incidence of adverse events (AEs) was higher with canagliflozin + HCTZ (69%) than with canagliflozin (47%) or HCTZ (50%) alone; most AEs were of mild severity. Overall, minimal changes in serum electrolytes (eg, sodium, potassium) were observed after coadministration of canagliflozin + HCTZ compared with individual treatments.
  
  
  CONCLUSIONS
  Adding canagliflozin treatment to healthy participants on HCTZ treatment had no notable pharmacokinetic or pharmacodynamic effects; canagliflozin coadministered with HCTZ was generally well tolerated, with no unexpected tolerability concerns. ClinicalTrials.gov identifier: NCT01294631.
authors.affiliation: Janssen Research & Development, LLC, Raritan, New Jersey. Electronic address: ddevinen@its.jnj.com.
authors.forename: Damayanthi
authors.initials: D
authors.lastname: Devineni
authors.affiliation: Janssen Research & Development, LLC, Raritan, New Jersey.
authors.forename: Nicole
authors.initials: N
authors.lastname: Vaccaro
authors.affiliation: Janssen Research & Development, LLC, San Diego, California.
authors.forename: David
authors.initials: D
authors.lastname: Polidori
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Rusch
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Ewa
authors.initials: E
authors.lastname: Wajs
mesh_terms: D000293:Adolescent; D000328:Adult; D001769:Blood / Q000187:drug effects; D000068896:Canagliflozin; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000009:adverse effects*; D005260:Female; D005960:Glucosides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D014556:Urine / Q000502:physiology; D055815:Young Adult
chemical_list: D005960:Glucosides; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; D006852:Hydrochlorothiazide; D000068896:Canagliflozin
keywords: canagliflozin; diuretic; drug–drug interaction; hydrochlorothiazide; pharmacodynamics; pharmacokinetics; sodium glucose co-transporter 2 (SGLT2) inhibitor; type 2 diabetes mellitus