By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a new indication for tolvaptan as the first treatment in patients with rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan, an oral selective vasopressin V2-receptor antagonist, was approved in 2009 for the treatment of hypervolemic and euvolemic hyponatremia. The FDA designated the new indication for tolvaptan with a priority review. It is marketed as JYNARQUE.
Tolvaptan is indicated to slow kidney function decline in adults at risk of rapidly progressing ADPKD.1
The recommended starting dose is 60 mg daily (45 mg on waking and 15 mg eight hours later).1 The dose is titrated to 60 mg and 30 mg and 90 mg and 30 mg, with at least one-week intervals between titrations if tolerated. Use with a strong CYP3A inhibitor is contraindicated. The dose should be reduced if used concomitantly with moderate CYP3A inhibitors. Enough water intake is encouraged to avoid thirst or dehydration. Tolvaptan is available as 15 mg, 30 mg, 45 mg, 60 mg, and 90 mg tablets.
Tolvaptan is the first approved treatment in the United States for rapidly progressing ADPKD.
Adverse reactions associated with tolvaptan were related to increased aquaresis.2 These include thirst, polyuria, and polydipsia. Approximately 15.4% of subjects in the three-year trial discontinued tolvaptan compared to 5% for placebo (8.3% vs. 1.2% because of aquaresis effects).2 Patients in earlier stages of disease may be more sensitive to aquaretic symptoms.3 The tolerability appears to stabilize by month four. A higher percentage of subjects on tolvaptan exhibited elevation of liver enzymes. The frequency of ALT elevation at three times the upper limit of normal was 4.9% for tolvaptan compared to 1.1% for placebo.1 Serious and potentially fatal liver injury has been reported.1 Monitoring of liver enzymes before and after initiation of treatment is recommended.
Tolvaptan has been reported to slow the growth of cysts, kidney volume, renal function decline, and the progression of the disease. Its efficacy was demonstrated in two Phase III, randomized, double-blind, placebo-controlled, clinical trials.1,2,4 One study included subjects at earlier stages of disease, while the second study included subjects in later stages. The first was a three-year study that included 961 subjects who received tolvaptan and 483 who received placebo. Subjects demonstrated a mean glomerular filtration rate (eGFR) of about 82 mL/min/1.73 m2, a mean height-adjusted total kidney volume (TKV) of 972 mL, and a mean age of 40 years.1,2 The primary endpoint was the rate of change of TKV normalized as a percentage. A key secondary composite endpoint was time to ADPKD-related events, including metrics for worsening kidney function, medically significant kidney pain, worsening hypertension, or worsening albumin/creatinine ratio. During the three-year period, TKV increased by 2.8% per year with tolvaptan and 5.5% with placebo. The largest effect was observed in the first year with little effect beyond that.1 ADPKD-related events decreased by 13.5% (44 vs. 50 events per 100 person-years), with the greatest benefit in worsening of kidney function (4.7 vs. 7.3). For the one-year study, in subjects with later-stage ADPKD (mean estimated eGFR of 41 mL/min/173 m2), tolvaptan slowed the change of eGFR from baseline.1,3 For tolvaptan, change was -2.34 mL/min/1.73 m2 vs. -3.61 mL/min/1.73 m2 for placebo (difference of 1.27 mL/min/1.73 m2; 95% confidence interval, 0.86-1.68; P < 0.001). Those < 55 years of age, white, and with baseline eGFR > 45 mL/min/1.73 m2 tended to accrue greater benefit.
ADPKD is an inherited disorder caused by mutation in either of the two genes that affect tubular and vascular development in the kidney and other organs, which can lead to slow growth of fluid-filled cysts in the kidney.5 The disease begins in utero, but cannot be detected for several decades. The uncontrolled growth of cysts leads to obstruction of renal tubules, blood vessels, and lymphatics. This causes fibrosis, kidney enlargement, kidney pain, hypertension, and, ultimately, end-stage failure. It is the fourth leading cause of end-stage failure in the United States.4 There is no cure or treatment for this condition. Tolvaptan is the first U.S.-approved treatment that is indicated to slow the progression of the disease. The cost for a 28-day supply, regardless of dose, is $13,041.10. It is available only through a restricted distribution program called the JYNARQUE REMS Program.
- JYNARQUE Prescribing Information. Otsuka Pharmaceutical Co., April 2018. Available at: . Accessed May 23, 2018.
- Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367:2407-2418.
- Devuyst O, Chapman AB, Shoaf SE, et al. Tolerability of aquaretic-related symptoms following tolvaptan for autosomal dominant polycystic kidney disease: Results from TEMPO 3:4. Kidney Int Rep 2017;2:1132-1140.
- Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med 2017;377:1930-1942.
- Grantham JJ. Clinical practice. Autosomal dominant polycystic kidney disease. N Engl J Med 2008;359:1477-1485.