Lixivaptan, a non-peptide vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia.

Lixivaptan (VPA-985), being developed by Biogen Idec and Cardiokine, under license from Wyeth (now part of Pfizer), is a non-peptide, selective vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia associated with heart failure. Arginine vasopressin, the native V2 receptor ligand, stimulates water reabsorption via activation of V2 receptors that are expressed in the collecting ducts of the kidney. In preclinical studies, lixivaptan displayed competitive antagonist activity at V2 receptors in vitro, and increased urine volume and decreased urine osmolality in rats and dogs. The therapeutic benefits of lixivaptan are being evaluated in patients with conditions that are associated with water excess and hyponatremia. Phase II clinical trials in patients with congestive heart failure, liver cirrhosis with ascites or syndrome of inappropriate antidiuretic hormone have demonstrated that, unlike traditional diuretics, lixivaptan increases water clearance without affecting renal sodium excretion or activating the neurohormonal system. Administration of lixivaptan in combination with the diuretic furosemide has been tested in rats as well as in trials in healthy volunteers, in which the two agents were well tolerated. Ongoing phase III trials will determine the role of lixivaptan in the management of hyponatremia, especially when associated with heart failure.