Pharmacodynamic effects of a nonpeptide antidiuretic hormone V2 antagonist in cirrhotic patients with ascites

Abstract

Water retention and dilutional hyponatremia, mainly attributable to an impairment of free water excretion and increased vasopressin activity, are well-documented complications in cirrhotic patients with ascites. VPA-985 is a selective, nonpeptide, orally active, vasopressin-2-receptor antagonist. The aim of this study was to determine the pharmacodynamics, safety, and pharmacokinetics of ascending single doses (25, 50, 100, 200, and 300 mg) in cirrhotic patients with ascites in a randomized, double-blind, placebo-controlled trial. Each dose level was studied in 5 patients (4 active and 1 placebo). After an overnight fast and fluid restriction (continued for 4 hours after dose administration), all patients were given placebo on baseline day and an oral suspension of VPA or placebo on the following day. VPA produced a significant dose-related increase in daily urine output (1,454 ؎ 858 mL to 4,568 ؎ 4,385 mL with VPA 300 mg) and a dose-related decrease in urine osmolality. The free water clearance reached greater than 3 mL/min for doses 100 mg or greater. Simultaneously, significant increases in serum osmolality, sodium, and vasopressin levels were found. There was a significant increase in sodium urine excretion. VPA was rapidly absorbed and maximum serum concentrations were achieved within 1 hour after administration. I n normal individuals, the administration of a water load (20 mL/kg body weight of 5% glucose intravenously or water orally over 45 min) is followed by an increase in the excretion of a hypotonic (Ͻ100 mOsm/ kg) urine flow responsible for an increase in free water clearance (FWC) reaching 6 to 12 mL/min. Cirrhotic patients without ascites have normal water handling. 1 Up to 75% of cirrhotic patients with ascites, however, have moderate reduction (1-6 mL/min) of FWC after a water load. In approximately 30% of cases, the impairment is severe (Ͻ1 mL/min after water load) leading to spontaneous hyponatremia because those patients are unable to excrete regular water intake. 2 Hyponatremia can also be triggered or aggravated by the use of diuretics in about 25% of cases. Pathophysiologic mechanisms leading to water overload are not fully understood, but several factors may be involved, among them: (1) reduced delivery of filtrate to the ascending limb of the loop of Henle, secondary to enhancement of proximal sodium reabsorption and decrease of glomerular filtration rate; (2) reduced renal synthesis of prostaglandins; and (3) increased secretion of antidiuretic hormone. 3 There is some evidence to indicate that increased plasma arginine vasopressin (AVP) concentration plays a major role: a correlation between plasma AVP levels and the magnitude of FWC impairment 4 ; the temporal relationship between impairment of water excretion and vasopressin hypersecretion in rats with experimental cirrhosis; 5 the aquaretic effect of -opioid agonists, which act through inhibition of AVP release

Sodium Excretion in Response to Vasopressin and Selective Vasopressin Receptor Antagonists

“…A significant three-and five-fold increase in sodium excretion with 10 and 30 but not with 1 and 3 mg/kg BW was also reported in the previous studies of the first nonpeptide V2R antagonist, OPC-31260. 27 VPA 985, another V2R antagonist, increased sodium excretion significantly in patients with hyponatremia and cirrhosis ascites 28,29 but not in patients with the syndrome of inappropriate secretion of antidiuretic hormone. 28 SR121463A was also shown to increase sodium excretion chronically in rats with cirrhosis.…”

Hyponatremia in cirrhosis: Pathogenesis, clinical significance, and management

“…The first studies on vaptans in cirrhosis were performed in patients with ascites but without hyponatremia. 37,41 In this population, the oral administration of vaptans is associated with a marked increase in urine volume, reduction in urine osmolality, and increase in solute-free water excretion, which is responsible for a negative fluid balance. Urine sodium excretion does not change significantly.…”

Vasopressin receptor antagonists

“…This has also been seen in patients with cirrhosis 11,12 and in patients with hyponatremia secondary to SIADH. 13,14 In a study by Wong et al, 44 hospitalized patients (33 patients with cirrhosis, 6 with CHF, and 5 with SIADH) were studied on a constant sodium intake, with lixivaptan doses of 25, 125, and 250 mg twice daily or placebo.…”

“…Although these agents are proving to be of some clinical benefit, further studies are required to assess the safety profile of the long-term use of vasopressin receptor antagonists. Grebes et al 10 Decaux et al 13 Guyader et al 11 Wong Gheorghiade et al 16 Gheorghiade et al 17 Gheorghiade …”