Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Jul 21;2(6):1132-1140.
doi: 10.1016/j.ekir.2017.07.004. eCollection 2017 Nov.

Tolerability of Aquaretic-Related Symptoms Following Tolvaptan for Autosomal Dominant Polycystic Kidney Disease: Results From TEMPO 3:4

Olivier Devuyst  1   2 , Arlene B Chapman  3 , Susan E Shoaf  4 , Frank S Czerwiec  4 , Jaime D Blais  4
Affiliations

Tolerability of Aquaretic-Related Symptoms Following Tolvaptan for Autosomal Dominant Polycystic Kidney Disease: Results From TEMPO 3:4

Olivier Devuyst et al. Kidney Int Rep. .

Abstract

Introduction: In the randomized placebo-controlled Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial, tolvaptan slowed kidney growth and renal function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD). Consistent with its primary pharmacologic activity, tolvaptan use was commonly associated with aquaretic adverse events (AAEs) attributable to excess free water clearance.

Methods: A post hoc analysis of tolvaptan-related discontinuations from the pivotal randomized controlled trial TEMPO 3:4 and its open-label extension TEMPO 4:4.

Results: In total, 750 of 961 tolvaptan-treated subjects (78%) in TEMPO 3:4 reported at least one AAE. Of these 750 subjects, 72 (10%) discontinued because of an AAE (aquaretic-discontinued group) and 573 (76%) continued (aquaretic-continued group). The aquaretic-discontinued subjects were younger, had better baseline renal function, and had higher fasting urine osmolality than aquaretic-continued subjects. Of the 750 subjects reporting an AAE, 105 (14%) discontinued for another reason (non-aquaretic-discontinued group). Compared to non-aquaretic-discontinued subjects, aquaretic-discontinued subjects were more commonly male, had better baseline renal function, and discontinued the study drug faster. After 3 years of therapy, 75% of tolvaptan subjects indicated that they could tolerate their current dose for the rest of their lives, compared to 85% of placebo subjects. These findings were corroborated by results in the open-label extension trial TEMPO 4:4.

Discussion: In this study, AAEs were common but well tolerated in ADPKD patients on tolvaptan. ADPKD patients in earlier stages of disease progression may be more sensitive to aquaretic symptoms, which may help in guiding tolvaptan dosing and titration decisions in the future.

Keywords: aquaretic adverse events; autosomal dominant polycystic kidney disease; discontinuation; drug safety; tolerability; tolvaptan.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Flow chart of tolvaptan subjects into categories of participants who reported or did not report an aquaretic adverse event (AAE). (a) Tolvaptan subjects in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial. (b) Prior placebo subjects in TEMPO 4:4. AC, aquaretic-continued; AD, aquaretic-discontinued; AE, adverse event; NAD, non–aquaretic discontinued.
Figure 2
Figure 2
Urine osmolality in tolvaptan subjects who reported an aquaretic adverse event (AAE). All patient data points are plotted as circles. Box plot shows mean and interquartile range of fasting baseline urine osmolality. AC, aquaretic-continued; AD, aquaretic-discontinued; AE, adverse event; Discont., discontinued; max, maximum; min, minimum; NAD, non–aquaretic-discontinued.
Figure 3
Figure 3
Frequency of aquaretic adverse events that led to trial discontinuation of tolvaptan subjects in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial. Nocturia, need to wake up to urinate at night; pollakiuria, abnormally frequent urination; polydipsia, excessive thirst; polyuria, production of large volumes of dilute urine.
Figure 4
Figure 4
Dose of tolvaptan at discontinuation relative to the highest titrated dose in aquaretic-discontinued (AD) subjects. Subjects were titrated to the highest tolerated dose of 45/15, 60/30, or 90/30 mg/d and were permitted to down-titrate as needed during the trial. The highest titrated dose is plotted on the x-axis, and the dose at the time of discontinuation (90/30, 60/30, 45/15, < 45/15 mg/d) is plotted as a box plot based on percentage of patients. (a) Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4. (b) TEMPO 4:4.
Figure 5
Figure 5
Time to discontinuation due to aquaretic and non-aquaretic adverse events. Box plot of median and interquartile range of time to discontinuation in the aquaretic-discontinued (AD) and non–aquaretic-discontinued (NAD) groups. Data points above and below the 75th and 25th quartiles are depicted in black circles. The overall ranges were 2 to 877 days in the AD group and 8 to 1050 days in the NAD group. Discont., discontinued; max, maximum; min, minimum; TEMPO 3:4, Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes.
Figure 6
Figure 6
Percentage of subjects tolerating their current dose of study drug during the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial. 3w, 3 weeks (refers to the time point taken at the end of the titration period).
See this image and copyright information in PMC

References

    1. Grantham J.J. Clinical practice. Autosomal dominant polycystic kidney disease. N Engl J Med. 2008;359:1477–1485. - PubMed
    1. Torres V.E., Harris P.C., Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007;369:1287–1301. - PubMed
    1. Grantham J.J., Mulamalla S., Swenson-Fields K.I. Why kidneys fail in autosomal dominant polycystic kidney disease. Nat Rev Nephrol. 2011;7:556–566. - PubMed
    1. Ong A.C., Devuyst O., Knebelmann B. Autosomal dominant polycystic kidney disease: the changing face of clinical management. Lancet. 2015;385:1993–2002. - PubMed
    1. United States Renal Data System: 2014 annual data report: an overview of the epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda, MD: 2014.