title: Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias.
abstract: BACKGROUND
  Tolvaptan, a nonpeptide selective vasopressin receptor (V2) antagonist, is in development for the treatment of congestive heart failure and hyponatremia. Tolvaptan is primarily metabolized via CYP3A4. This study was conducted to determine the extent of the pharmacokinetic interaction between tolvaptan and steady state amiodarone, an antiarrhythmic drug commonly prescribed for patients with congestive heart failure and a known inhibitor of other drugs metabolized by CYP3A4.
  
  
  METHODS
  This was a multicenter, open-label, 1-arm, 3-period, sequential treatment study conducted in 11 men (10) and women aged 49 to 80 years. They were primarily Caucasian (20) subjects, with a history of cardiac arrhythmias who were otherwise healthy. Subjects were to have been on oral amiodarone maintenance therapy of 200 mg/day for at least 10 months. All subjects took 200 mg amiodarone once daily on each study day; on days 3 and 4, they were also coadministered 30 and 90 mg of tolvaptan, respectively. The plasma concentrations of amiodarone and its metabolite desethylamiodarone were determined for 24 hours postdose on days 2, 3, and 4, tolvaptan concentrations were determined for 24 hours postdose on days 3 and 4.
  
  
  RESULTS
  As determined by the ratio of the geometric means and 90% confidence intervals (0.5 to 2.0) for the maximal plasma concentration and the area under the curve during the dosing interval for both amiodarone and desethylamiodarone, tolvaptan coadministration had no effect on either amiodarone and desethylamiodarone disposition, as all the geometric mean ratios (amiodarone + tolvaptan [30 or 90 mg] vs amiodarone alone) were approximately 1.
  
  
  CONCLUSIONS
  Tolvaptan coadministration does not alter steady-state amiodarone or desethylamiodarone concentrations. Tolvaptan concentrations did not appear to be different from historical controls. The most frequently reported adverse event was polyuria (15 of 21 subjects for amiodarone + 30 mg tolvaptan); an expected outcome due to the known potent aquaretic action of tolvaptan. The combination of amiodarone and tolvaptan was well tolerated.
authors.affiliation: Otsuka Maryland Research Institute, Rockville, MD 20850, USA. susans@otsuka.com
authors.forename: Susan Elizabeth
authors.initials: SE
authors.lastname: Shoaf
authors.forename: Marcelo Víctor
authors.initials: MV
authors.lastname: Elizari
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.forename: Kumara
authors.initials: K
authors.lastname: Sekar
authors.forename: Liliana Rosa
authors.initials: LR
authors.lastname: Grinfeld
authors.forename: N Alejandro
authors.initials: NA
authors.lastname: Barbagelata
authors.forename: Jorge
authors.initials: J
authors.lastname: Lerman
authors.forename: Steven Lee
authors.initials: SL
authors.lastname: Bramer
authors.forename: Jorge
authors.initials: J
authors.lastname: Trongé
authors.forename: Cesare
authors.initials: C
authors.lastname: Orlandi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000638:Amiodarone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065092:Antidiuretic Hormone Receptor Antagonists; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D001552:Benzazepines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077602:Tolvaptan
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan; D000638:Amiodarone