Pharmacokinetics and Pharmacodynamics of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Phase 2 Trials for Dose Selection in the Pivotal Phase 3 Trial.

• Type of Material: Article
• Authors: Susan E. Shoaf, Otsuka Pharmaceutical Development & Commercialization; Arlene Chapman, Emory University; Vicente E. Torres, Mayo Clinic; John Ouyang, Otsuka Pharmaceutical Development & Commercialization; Frank S. Czerwiec, Otsuka Pharmaceutical Development & Commercialization
• Language: English
• Date: 2017-07
• Publisher: Wiley
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/jcph.880
• Title of Journal or Parent Work: Journal of Clinical Pharmacology
• ISSN: 0091-2700
• Volume: 57
• Issue: 7
• Start Page: 906
• End Page: 917
• Keywords: autosomal dominant polycystic kidney disease; urine osmolality; pharmacokinetics; pharmacodynamics; Tolvaptan; tolerability
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pharmacology

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 Uosm to <300 mOsm/kg for 24 hours. The 45/15-mg regimen was well tolerated and effective in suppressing Uosm in >50% of subjects. Therefore, this regimen was selected as the starting regimen for the TEMPO 3:4 trial. The 90/30-mg regimen suppressed Uosm in 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.