title: Pharmacokinetics and Pharmacodynamics of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Phase 2 Trials for Dose Selection in the Pivotal Phase 3 Trial.
abstract: In the pivotal TEMPO 3:4 trial, the arginine vasopressin V2-receptor antagonist tolvaptan reduced the rate of kidney growth in patients with autosomal dominant polycystic kidney disease. Tolvaptan was initiated as daily morning/afternoon doses of 45/15 mg, and uptitrated weekly to 60/30 mg and 90/30 mg according to patient-reported tolerability. The current report describes 3 phase 2 trials in adult autosomal dominant polycystic kidney disease subjects that were the basis for the titrated split-dose regimen: a single ascending-dose trial (tolvaptan 15 to 120 mg; n = 11), a multiple split-dose trial (tolvaptan 15/15 mg, 30/0 mg, 30/15 mg, and 30/30 mg; n = 37), and an 8-week open-label safety and efficacy trial in 46 of the 48 subjects who participated in the prior 2 trials (tolvaptan 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg). Urine osmolality (Uosm) was chosen as the biomarker of V2 receptor inhibition. Two tolvaptan doses per day were necessary to suppress Uosmto <300 mOsm/kg for 24 hours. The 45/15-mg regimen was well tolerated and effective in suppressing Uosmin >50% of subjects. Therefore, this regimen was selected as the starting regimen for the TEMPO 3:4 trial. The 90/30-mg regimen suppressed Uosmin 85% of subjects tested; however, only 28/46 subjects agreed to uptitrate to 90/30 mg due to tolerability. Higher concentrations of tolvaptan were less well tolerated, resulting in adverse events of pollakiuria, thirst, polyuria, nocturia, and a higher number of times out of bed to urinate. Subjects who agreed to uptitrate to 90/30 mg had lower eGFR than those who did not uptitrate.
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Rockville, MD, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Shoaf
authors.affiliation: Division of Nephrology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Rockville, MD, USA.
authors.forename: John
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Rockville, MD, USA.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Czerwiec
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001552:Benzazepines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy*; D000077602:Tolvaptan
chemical_list: D001552:Benzazepines; D000077602:Tolvaptan
keywords: Tolvaptan; autosomal dominant polycystic kidney disease; pharmacodynamics; pharmacokinetics; tolerability; urine osmolality