Tolvaptan is a selective vasopressin V₂ receptor antagonist that blocks binding of arginine vasopressin (AVP) to V₂ receptors in collecting duct of kidney, thereby inducing water diuresis (aquaresis) without depletion of electrolytes. Tolvaptan was firstly approved as an aquaretic agent for treatment of hyponatremia including syndrome of inappropriate secretion of antidiuretic hormone and for treatment of fluid volume overload in heart failure and cirrhosis.
Tolvaptan was also approved for ADPKD. ADPKD is the most common genetic kidney disease and caused by mutations in PKD1 or PKD2. Fluid-filled cysts develop and enlarge in both kidneys, eventually leading to kidney failure. Several signaling pathways have been demonstrated in the pathogenesis of ADPKD. cAMP plays an important role in cyst growth by promoting cell proliferation and fluid secretion. Antagonism of AVP by tolvaptan suppressed AVP-induced cAMP production and renal cyst growth. In some animal models, tolvaptan showed suppression of cyst growth and renal injury, and delayed the onset of end-stage renal disease.
In the Phase 3 clinical trial in ADPKD patients (TEMPO 3:4), 3-year treatment with tolvaptan slowed the disease progression including increase of kidney volume and decline in renal function. The therapeutic efficacy of tolvaptan in patients with late-stage ADPKD was confirmed in another 1-year Phase 3 REPRISE trial.
Tolvaptan is a first and only approved drug for treatment of ADPKD and it provides therapeutic option to suppress both cyst growth and decline of kidney function across the globe.