A Randomized Trial of Modified-Release Versus Immediate-Release Tolvaptan in ADPKD

Abstract

Introduction: Tolvaptan, for treatment of autosomal dominant polycystic kidney disease (ADPKD), is provided as immediate-release (IR) tablets administered twice daily in split-dose regimens to suppress urine osmolality to <300 mOsm/kg. A modified-release (MR) formulation was developed for once-daily (QD) dosing to increase compliance and mitigate urinary symptom burden. This phase 2, dose-ranging study (NCT01210560) compared pharmacokinetics, pharmacodynamics, and tolerability of several MR regimens with IR in patients with ADPKD.

Methods: This was a multicenter, parallel-arm, randomized, crossover, double-blind, placebo-controlled trial. Each of 2 study arms had 12 subjects and 3 crossover periods. Dose regimens were administered for 7 days; placebo-masked QD versus split-dose treatments. Endpoints included pharmacokinetic parameters, percentage of subjects with urine osmolality <300 mOsm/kg, urine volume, number of daily urine voids, and tolerability.

Results: Tolvaptan MR 20 to 120 mg exhibited dose-proportional pharmacokinetics. Percentage of subjects with spot urine osmolality <300 mOsm/kg increased with dose, with tolvaptan MR 120 mg and IR 90+30 mg each suppressing 91.7% of subjects below this level. Urinary burden on the ADPKD Nocturia Quality of Life, ADPKD Urinary Urgency, and ADPKD Urinary Frequency Questionnaires correlated with tolvaptan exposure, with high interindividual variability in responses. Changes in questionnaire scores were sensitive to changes in urine volume but not proportional to volume change, reflecting differences in subject tolerance to increased urine volume.

Conclusion: Tolvaptan MR exhibited predictable and dose-proportional pharmacokinetics and no improvement in tolerability versus tolvaptan IR. Tolerability of the urinary effects of treatment within the high-dose MR and IR groups exhibited substantial interindividual variability.

Keywords: autosomal dominant polycystic kidney disease; clinical trial; pharmacodynamics; pharmacokinetics; tolvaptan.

Graphical abstract

Figure 1

Study design. ∗Doses were administered at approximately 0800 and 1600 hours. Placebo capsules and tablets were used to mask split dosing versus once-daily dosing. D, day; IR, immediate release; MR, modified release.

Figure 2

Median plasma tolvaptan concentration-time curves on day 7 of tolvaptan treatment for 5 different dosage regimens in subjects with autosomal dominant polycystic kidney disease. Green box indicates range of tolvaptan concentrations that are minimally effective to maximally saturating for increasing urine excretion rate. IR, immediate release; MR, modified release.

Figure 3

Percentage of subjects with spot urine osmolality <300 mOsm/kg following 7 days of tolvaptan treatment for 5 different dosage regimens in subjects with autosomal dominant polycystic kidney disease. IR, immediate release; MR, modified release.

Figure 4

Mean (±SD) urine osmolality values at baseline (day 0) and on day 7 of tolvaptan treatment in subjects with autosomal dominant polycystic kidney disease. Data points are staggered for legibility. IR, immediate release; MR, modified release.

Figure 5

Mean (±SD) 24-hour urine volume (a) and number of daytime urine voids (b) at baseline and day 7 of tolvaptan treatment. As the initial treatment regimens in group 1, tolvaptan modified release (MR) 120 mg and immediate release (IR) 90+30 mg had the same baseline values.

Figure 6

Mean (±SD) nocturia interference score from the Nocturia Quality-of-Life Questionnaire (range: 0 = not at all; 10 = a great deal) at baseline and day 6 of tolvaptan treatment (a) and number of nighttime urine voids at baseline and day 7 of tolvaptan treatment (b). As the initial treatment regimens in group 1, tolvaptan modified release (MR) 120 mg and immediate release (IR) 90+30 mg had the same baseline values.