title: Pharmacokinetics, pharmacodynamics, and safety of tolvaptan, a nonpeptide AVP antagonist, during ascending single-dose studies in healthy subjects.
abstract: Two single-center, double-blind, randomized, placebo-controlled, sequentially enrolled studies were conducted. In study 1, 8 subjects (6 active/2 placebo) received 60-, 90-, 120-, 180-, or 240-mg tolvaptan/matching placebo. In study 2, 9 subjects (6 active/3 placebo) received 180-, 240-, 300-, 360-, 420-, or 480-mg tolvaptan/matching placebo. Increases in tolvaptan C(max) were less than dose-proportional and plateaued at doses greater than 240 mg; AUC(infinity) increased proportionally with dose. Changes in serum K(+), creatinine clearance, and Na(+), K(+), and osmolality urinary excretion were similar to the placebo group for the 0- to 24-hour interval following dosing. Changes were observed in plasma arginine vasopressin, serum aldosterone, and plasma renin activity but were not clinically significant. Increases were seen in mean serum Na(+) concentrations (4-6 mEq/L), plasma osmolality ( approximately 8 mOsm/kg), and free water clearance ( approximately 6 mL/min) throughout 0 to 24 hours; none of these increases was dose dependent. Only total urine volume excretion (0-72 hours postdose) increased linearly with dose. As plasma tolvaptan concentrations increased, the duration that the urine excretion rate remained above baseline rates also increased. The most frequent adverse events--excess thirst, frequent urination, and dry mouth--appeared to be related to the pharmacological action of tolvaptan. No dose-limiting toxicities were observed.
authors.affiliation: Clinical Pharmacology, Otsuka Pharmaceutical Development & Commercialization, Inc, MD 20850, USA. susan.shoaf@otsuka.com
authors.forename: Susan E
authors.initials: SE
authors.lastname: Shoaf
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.forename: Patricia
authors.initials: P
authors.lastname: Bricmont
authors.forename: Suresh
authors.initials: S
authors.lastname: Mallikaarjun
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001552:Benzazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009481:Neurophysins / Q000037:antagonists & inhibitors*; D011498:Protein Precursors / Q000037:antagonists & inhibitors*; D013607:Tablets; D013894:Thirst / Q000187:drug effects; D000077602:Tolvaptan; D014554:Urination / Q000187:drug effects; D014667:Vasopressins / Q000037:antagonists & inhibitors*
chemical_list: C438657:AVP protein, human; D001552:Benzazepines; D009481:Neurophysins; D011498:Protein Precursors; D013607:Tablets; D014667:Vasopressins; D000077602:Tolvaptan