ASN 2010: Tolvaptan Effective on Dilutional Hyponatremia, Neuro Function

Researchers continue to evaluate the clinical merits of tolvaptan, a vasopressin receptor 2 antagonist approved by the Food and Drug Administration in May of 2009 and used in the treatment of hyponatremia. They have reported some recent abstracted findings to the American Society of Nephrology 43rd Annual Meeting and Scientific Exposition in Denver.

In a 2004 trial, tolvaptan was observed to increase excretion of excess fluids and improve blood sodium levels in heart failure patients when administered with traditional diuretics. This outcome was achieved without side effects such as hypotension or hypokalemia, and without detrimental effect to the kidney. Tolvaptan is now on the approval fast track for use in treating polycystic kidney disease.

When the drug was introduced as a therapy for the euvolemic and hypervolemic manifestations of hyponatremia, it challenged the vasopressin receptor antagonist conivaptan as the dominant treatment agent for these indications. A study conducted by the division of nephrology at Lenox Hill Hospital in New York shows that tolvaptan can successfully treat significant dilutional hyponatremia. Another collaborative group has reported that the agent can improve patient performance in neurocognitive and gait tests.

The first study reported experience with changes in SNa, urine osmolalities and AVP levels, before and after administration. Five patients with marked and less severe euvolemic and hypervolemic (kidney-related) hyponatremia were selected. Each patient received an initial oral dose of 15 mg tolvaptan. An additional 15 mg dose was given 24 hours after the initial dose if the patient failed to achieve an adequate response. The mean SNa increase was 7.4 mEq/L (range 2-11 mEq/L) in the first 24 hours following the initial tolvaptan dose. Two patients required one dose; two patients received two doses, and one patient required three doses to achieve a SNa level > 130 mEq/L.

There were no significant drops in blood pressure associated with tolvaptan administration. Urine osmolalities decreased a mean of 243 mOsm/kg H2O, and in patients that required repeated dosing they continued to be suppressed. The mean reported AVP level, pre-tolvaptan, was 7.6 pg/mL, and this changed by 0, -1, 1.5, and 26.7 pg/mL, respectively, with no data available for one patient.

In the second study, 57 subjects age 50 or older with asymptomatic chronic hyponatremia were randomized in a double blind treatment that used the Mini-Mental State Exam for evaluation of neurocognitive function. The mean age was 71 in both the tolvaptan and the placebo groups, and in each group, 30% were taking psycholpetic drugs and 30% were taking psychoanaleptic drugs.

Serum [Na ] rose from 129 to 136 for the tolvaptan patients and 130 to 132 for the placebo group, and fell afterward in both groups. Cognitive speed, the composite primary endpoint, improved by 0.39 for the tolvaptan patients and by 0.20 in placebo patients (z-score); this measure fell in both groups following withdrawal.

The overall neurocognitive composite measure favored the tolvaptan group nominally, but not statistically ( 0.12, p = 0.16). Elderly hyponatremic subjects showed improvement in some neurocognitive and gait tests, as well as markers of bone metabolism after treatment with tolvaptan. Researchers concluded that the results support published data indicating that tolvaptan can lead to improved neurological function.