ACCP Virtual Journal Club - Pharmacokinetics and Pharmacodynamics of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Phase 2 Trials for Dose Selection in the Pivotal Phase 3 Trial

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 (ADPKD). 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. Since publication of the TEMPO 3:4 trial, there has been interest in better understanding how this dosing regimen was developed so that the rationale for uptitration to the 90/30-mg dose regimen or to the highest tolerated dose are made in ADPKD patients on tolvaptan.

The article 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). 

After completing this activity, the learner will be able to:

1. Understand biomarkers related to vasopressin V2-receptor antagonist efficacy and safety
2. Fully comprehend and explain the PK-PD rationale behind dosing titrations with tolvaptan in ADPKD patients