Pharmacokinetic and Pharmacodynamic Interaction Between Tolvaptan, a Non-Peptide AVP Antagonist, and Furosemide or Hydrochlorothiazide

Abstract

The pharmacokinetic and pharmacodynamic interactions between tolvaptan and furosemide or hydrochlorothiazide (HCTZ) were determined in a single-center, randomized, open-label, parallel-arm, 3-period crossover study conducted in healthy white (Caucasian) men. A total of 12 subjects were enrolled in the study, with 6 subjects assigned to each of two treatment arms. Subjects in Arm 1 received 30 mg of tolvaptan, 80 mg of furosemide, and 30 mg of tolvaptan + 80 mg of furosemide. Subjects in Arm 2 received 30 mg of tolvaptan, 100 mg of HCTZ, and 30 mg pf tolvaptan + 100 mg of HCTZ. Doses were separated by a 48-hour washout. Blood and urine samples were collected at scheduled timepoints during the 24 hours after administration of study drug for the determination of pharmacokinetic and pharmacodynamic parameters. No clinically significant changes were noted in the pharmacokinetic profiles of tolvaptan and furosemide or tolvaptan and HCTZ when coadministered. Free water clearance, 24-hour urine volume, plasma sodium and argentine vasopressin concentrations, and plasma osmolality were higher, and urine osmolality was lower when tolvaptan was administered either alone or in combination with furosemide or HCTZ, compared with furosemide or HCTZ administered alone. At 24 hours postdose, plasma renin activity was increased after furosemide or HCTZ administered alone or with tolvaptan, but it was unchanged after tolvaptan alone. Tolvaptan did not significantly affect the natriuretic activity of furosemide or HCTZ. Furosemide and HCTZ did not significantly affect the aquaretic activity of tolvaptan. Tolvaptan administered alone or in combination with furosemide or HCTZ was safe and well tolerated at the given doses.