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 (U_osm ) was chosen as the biomarker of V2 receptor inhibition. Two tolvaptan doses per day were necessary to suppress U_osm to <300 mOsm/kg for 24 hours. The 45/15-mg regimen was well tolerated and effective in suppressing U_osm 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 U_osm 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.

Keywords: Tolvaptan; autosomal dominant polycystic kidney disease; pharmacodynamics; pharmacokinetics; tolerability; urine osmolality.

Figure 1

Subject disposition flow chart in Trial 250.

Figure 2

Median tolvaptan plasma concentrations in subjects with ADPKD following single doses (Trial 248) or on day 5 following split doses (Trial 249).

Figure 3

Mean urine osmolality (mOsm/kg) at the end of the collection interval following tolvaptan single doses (Trial 248) or multiple doses for 5 days (Trial 249) in subjects with ADPKD.

Figure 4

Urine osmolality vs urine excretion rate in 8 ADPKD subjects at baseline or following 120 mg tolvaptan.

Figure 5

Mean spot urine osmolality concentrations following multiple doses of tolvaptan in subjects with ADPKD (Trial 250).

Figure 6

Mean (SD) change from baseline 24‐hour urine volume following tolvaptan single doses (Trial 248) or multiple doses for 5 days (Trial 249) in subjects with ADPKD.