Vasopressin Receptor Vasopressin Receptor AntagonistsAntagonists

Alicia NotkinAlicia Notkin

July 17, 2007July 17, 2007

OutlineOutline

• IntroductionIntroduction

• ConivaptanConivaptan

• TolvaptanTolvaptan

• LixivaptanLixivaptan

• SatavaptanSatavaptan

• ConclusionConclusion

• ReferencesReferences

IntroductionIntroduction

• SIADH – AVP release is not fully suppressed as SIADH – AVP release is not fully suppressed as it would normally be in a setting of it would normally be in a setting of hypotonicityhypotonicity

• CHF – arterial under-distention & baroreceptor CHF – arterial under-distention & baroreceptor unloading inhibit vagal suppression of AVP (as unloading inhibit vagal suppression of AVP (as well as renin & catecholamines)well as renin & catecholamines)

• Cirrhosis – splanchnic vasodilatation Cirrhosis – splanchnic vasodilatation arterial arterial underfilling w/ non-osmotic release of AVPunderfilling w/ non-osmotic release of AVP

Introduction (cont.)Introduction (cont.)

• Even “asymptomatic” patients with Even “asymptomatic” patients with chronic SIADH may have subtle chronic SIADH may have subtle psychomotor impairmentspsychomotor impairments

• Association of hyponatremia w/ Association of hyponatremia w/ increased morbidity & mortality in increased morbidity & mortality in patients w/ liver, heart, or neurologic patients w/ liver, heart, or neurologic diseasedisease

IntroductionIntroduction

• Traditional SIADH treatments: water Traditional SIADH treatments: water restriction, salt +/- a loop diuretic, restriction, salt +/- a loop diuretic, increased osmole diet, increased osmole diet, demeclocycline, lithiumdemeclocycline, lithium

• Difficult to treat when urine Difficult to treat when urine osmolality is particularly highosmolality is particularly high

• Treat based on severity of Treat based on severity of hyponatremia (how low & how hyponatremia (how low & how symptomatic)symptomatic)

Introduction (cont.)Introduction (cont.)

• ADH receptor antagonists ADH receptor antagonists a a selective water diuresis (Na/K selective water diuresis (Na/K excretion is not affected – Na & K excretion is not affected – Na & K loss are features of chronic SIADH)loss are features of chronic SIADH)

• Urine osmolality will then decreaseUrine osmolality will then decrease

• Serum Na will then increaseSerum Na will then increase

Vasopressin Receptor Location Vasopressin Receptor Location & Functions (KI 2006)& Functions (KI 2006)

Structure of the Vasopressin Structure of the Vasopressin V2 Receptor (Brenner & Rector V2 Receptor (Brenner & Rector

2004)2004)

Signal Transduction Via the V2 Signal Transduction Via the V2 Receptor (Brenner & Rector Receptor (Brenner & Rector

2004)2004)

ConivaptanConivaptan

• Only vasopressin receptor Only vasopressin receptor antagonist available in the U.S.antagonist available in the U.S.

• Non-selective (V2 & V1a): potential Non-selective (V2 & V1a): potential for splanchnic vasodilatation w/ for splanchnic vasodilatation w/ subsequent hypotension or variceal subsequent hypotension or variceal bleeding b/c of V1a effects (so not bleeding b/c of V1a effects (so not tested in cirrhotics)tested in cirrhotics)

• IV formulation only b/c of potent cyt IV formulation only b/c of potent cyt P450 3A4 inhibition if given orally P450 3A4 inhibition if given orally (so used only for inpatients)(so used only for inpatients)

• Approved for euvolemic Approved for euvolemic hyponatremiahyponatremia

Conivaptan – J Clin Endo Metab Conivaptan – J Clin Endo Metab 20062006• 74 euvolemic (74%) or hypervolemic (26%) 74 euvolemic (74%) or hypervolemic (26%)

patients >/= 18 years w/ Na 115-130 mEq/l, patients >/= 18 years w/ Na 115-130 mEq/l, FBG < 275mg/dl, serum osm < 290 FBG < 275mg/dl, serum osm < 290 mosm/kg H20, no volume depletionmosm/kg H20, no volume depletion

• Excluded patients w/ uncontrolled htn or Excluded patients w/ uncontrolled htn or arrhythmias, hypotension, untreated thyroid arrhythmias, hypotension, untreated thyroid abnormalities or adrenal insufficiency, CrCl abnormalities or adrenal insufficiency, CrCl < 20 ml/min, LFTs > 5x normal, signs of < 20 ml/min, LFTs > 5x normal, signs of liver disease, HIV, those requiring emergent liver disease, HIV, those requiring emergent treatment, those on meds that cause or treatment, those on meds that cause or treat SIADHtreat SIADH

• RCT giving oral conivaptan, 40 or 80mg/d, or RCT giving oral conivaptan, 40 or 80mg/d, or placebo, given in 2 divided doses x 5 daysplacebo, given in 2 divided doses x 5 days

Conivaptan – J Clin Endo Metab Conivaptan – J Clin Endo Metab 20062006

• Fluid intake limited to 2L/24 hrsFluid intake limited to 2L/24 hrs

• 1* outcome: change from baseline in serum 1* outcome: change from baseline in serum Na area under the curveNa area under the curve

• Statistically significant change from Statistically significant change from baseline in serum Na AUC w/ both doses baseline in serum Na AUC w/ both doses (achieved in a statistically significant (achieved in a statistically significant shorter amount of time)shorter amount of time)

• AEs: HA, hypotension, nausea, constipationAEs: HA, hypotension, nausea, constipation

• Aquaretic effects persisted for at least 6hrsAquaretic effects persisted for at least 6hrs

TolvaptanTolvaptan

• Not yet available in the Not yet available in the U.S.U.S.

• V2 selective: blocks V2 selective: blocks binding of arginine binding of arginine vasopressin to the V2 vasopressin to the V2 receptors of the distal receptors of the distal nephron onlynephron only

• OralOral

Tolvaptan – NEJM 2006Tolvaptan – NEJM 2006

• Report of 2 RCT: SALT-1 & SALT-2 (Study of Report of 2 RCT: SALT-1 & SALT-2 (Study of Ascending Levels of Tolvaptan in Hyponatremia)Ascending Levels of Tolvaptan in Hyponatremia)

• Euvolemic or hypervolemic patients > 18 years Euvolemic or hypervolemic patients > 18 years w/ Na < 135 mmol/L & either chronic heart w/ Na < 135 mmol/L & either chronic heart failure, cirrhosis, or SIADH; mostly outpatientsfailure, cirrhosis, or SIADH; mostly outpatients

• Excluded patients w/ psychogenic polydipsia, Excluded patients w/ psychogenic polydipsia, head trauma, postop conditions, uncontrolled head trauma, postop conditions, uncontrolled hypothyroidism or adrenal insufficiency, or hypothyroidism or adrenal insufficiency, or medication-induced hyponatremiamedication-induced hyponatremia

Tolvaptan – NEJM 2006Tolvaptan – NEJM 2006

• Also excluded if: hypovolemic, recent Also excluded if: hypovolemic, recent MI, VT/VF, stroke, SBP < 90 mm Hg, Cr MI, VT/VF, stroke, SBP < 90 mm Hg, Cr > 3.5 mg/dl, Child-Pugh score > 10 > 3.5 mg/dl, Child-Pugh score > 10 (unless exception), Na < 120 mmol/L w/ (unless exception), Na < 120 mmol/L w/ neurologic impairment, severe neurologic impairment, severe pulmonary HTN, uncontrolled DM, pulmonary HTN, uncontrolled DM, neurologic disease, little chance of neurologic disease, little chance of short-term survival or unlikely to short-term survival or unlikely to tolerate fluid volume shiftstolerate fluid volume shifts

Tolvaptan – NEJM 2006Tolvaptan – NEJM 2006

• 223 given placebo, 225 given 223 given placebo, 225 given tolvaptantolvaptan

• Initial dose: 15mg qd, titrated to max Initial dose: 15mg qd, titrated to max of 60 based on serum Naof 60 based on serum Na

• Primary endpoints: change in the Primary endpoints: change in the average daily area under the curve average daily area under the curve for serum Na from baseline to day 4 for serum Na from baseline to day 4 & baseline to day 30& baseline to day 30

Baseline CharacteristicsBaseline Characteristics

Tolvaptan – NEJM 2006Tolvaptan – NEJM 2006

• Increase in average daily AUC for serum Na Increase in average daily AUC for serum Na was significantly greater in the tolvaptan was significantly greater in the tolvaptan groupgroup

• Also seemed to be improvement in self-Also seemed to be improvement in self-assessed mental component summary scoreassessed mental component summary score

• Dry mouth, thirst, as well as constipation, Dry mouth, thirst, as well as constipation, weakness, hyperglycemia, & urinary weakness, hyperglycemia, & urinary frequency were seen more in the tolvaptan frequency were seen more in the tolvaptan groupgroup

LixivaptanLixivaptan

• Not yet available in the U.S.Not yet available in the U.S.

• V2 selectiveV2 selective

• OralOral

• Gastroenterology 2003 – RCT of 66 Gastroenterology 2003 – RCT of 66 patients w/ cirrhosis & hyponatremia (no patients w/ cirrhosis & hyponatremia (no SIADH or CHF); assigned to 100 or SIADH or CHF); assigned to 100 or 200mg/d of lixivaptan or placebo, plus 1L 200mg/d of lixivaptan or placebo, plus 1L fluid restriction, until Na >/= 136 or 7 daysfluid restriction, until Na >/= 136 or 7 days

Lixivaptan (cont.)Lixivaptan (cont.)

• Statistically significant difference in Statistically significant difference in the # of patients achieving a normal the # of patients achieving a normal serum Na compared to placeboserum Na compared to placebo

• Significant reduction in Uosm & body Significant reduction in Uosm & body weightweight

• Significant increase in thirst in the Significant increase in thirst in the high dose grouphigh dose group

Lixivaptan (cont.)Lixivaptan (cont.)

• Hepatology 2003 – 44 hospitalized patients w/ Hepatology 2003 – 44 hospitalized patients w/ Na < 130 mmol/L (5 w/ SIADH, 33 w/ cirrhosis, Na < 130 mmol/L (5 w/ SIADH, 33 w/ cirrhosis, 6 w/ CHF), given 25, 125, or 250mg 2x/d or 6 w/ CHF), given 25, 125, or 250mg 2x/d or placebo; doses held for excessive Na rise, placebo; doses held for excessive Na rise, dehydration, encephalopathydehydration, encephalopathy

• Significant response (increased water Significant response (increased water clearance and serum Na) compared to clearance and serum Na) compared to placebo; significant dose related increase in placebo; significant dose related increase in NaNa

• Higher doses Higher doses significant dehydration significant dehydration

SatavaptanSatavaptan

• Not yet available in the U.S.Not yet available in the U.S.• V2 selectiveV2 selective• OralOral• CJASN 2006 – 34 patients treated w/ CJASN 2006 – 34 patients treated w/

satavaptan 25mg, 50mg, or placebo x 5 satavaptan 25mg, 50mg, or placebo x 5 days days 23 days of open-label dosage- 23 days of open-label dosage-adjustment periodadjustment period

• Statistically significant response in Statistically significant response in treatment group re. Na normalization or treatment group re. Na normalization or increase by >/= 5mmol/Lincrease by >/= 5mmol/L

ConclusionConclusion

• Vasopressin receptor antagonists can Vasopressin receptor antagonists can cause an electrolyte-free aquaresis, cause an electrolyte-free aquaresis, reduce urine osmolality, & raise serum reduce urine osmolality, & raise serum NaNa

• Risk of overly rapid correction of Risk of overly rapid correction of hyponatremia seems lowhyponatremia seems low

• Main side effect is increased thirstMain side effect is increased thirst

• Tachyphylaxis does not seem to occurTachyphylaxis does not seem to occur

Conclusion (cont.)Conclusion (cont.)

• Possibility of hypotension & variceal Possibility of hypotension & variceal bleeding in cirrhotics if given a V1aR bleeding in cirrhotics if given a V1aR blockerblocker

• ? Bleeding complications from V2R ? Bleeding complications from V2R inhibition in vascular endotheliuminhibition in vascular endothelium

• ? Role in CHF mortality – data ? Role in CHF mortality – data conflictingconflicting

• $ v. benefit$ v. benefit

Conclusion (cont.)Conclusion (cont.)

• PCKD – polycystin defects may promote cyst PCKD – polycystin defects may promote cyst development b/c they development b/c they increases in increases in intracellular cAMP (a second messenger for intracellular cAMP (a second messenger for AVP acting at the V2R) – therefore, V2R AVP acting at the V2R) – therefore, V2R antagonists may antagonists may reduced cyst volume reduced cyst volume

• Congenital NDI – type 2 V2R mutations Congenital NDI – type 2 V2R mutations cause misfolding & interfere w/ trafficking of cause misfolding & interfere w/ trafficking of the receptor from the ER to the cell the receptor from the ER to the cell membrane – VRA can bind to misfolded membrane – VRA can bind to misfolded intracellular V2R & improve transport to the intracellular V2R & improve transport to the cell membranecell membrane

ReferencesReferences• Abraham, WT et al. Aquaretic effect of lixivaptan, an oral, non-peptide, selective V2 receptor Abraham, WT et al. Aquaretic effect of lixivaptan, an oral, non-peptide, selective V2 receptor

vasopressin antagonist, vasopressin antagonist, in New York Heart Association functional class II and III chronic heart in New York Heart Association functional class II and III chronic heart failure patients. JACC 2006; failure patients. JACC 2006; 47(8):1615.47(8):1615.

• Gerbes, AL et al. Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a Gerbes, AL et al. Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-randomized double- blind multicenter trial. blind multicenter trial. GastroenterologyGastroenterology 2003; 124:933. 2003; 124:933.

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• Gheorghiade, M et al. Effects of tolvaptan, a vasopressor antagonist, in patients hospitalized with Gheorghiade, M et al. Effects of tolvaptan, a vasopressor antagonist, in patients hospitalized with worsening heart worsening heart failure: a randomized controlled trial. failure: a randomized controlled trial. JAMAJAMA 2004; 291:1963. 2004; 291:1963.

• Gheorghiade, M et al. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart Gheorghiade, M et al. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results failure: results from a double-blind, randomized trial. from a double-blind, randomized trial. CirculationCirculation 2003; 107:2690. 2003; 107:2690.

• Konstam, MA et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the Konstam, MA et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST EVEREST outcome trial. outcome trial. JAMAJAMA 2007; 297:1319. 2007; 297:1319.

• Renneboog, B et al. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention Renneboog, B et al. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. deficits. Am J Am J MedMed 2006; 119:71. 2006; 119:71.

• Schrier, RW et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. Schrier, RW et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. NEJMNEJM 2006; 2006; 355:2099. 355:2099.

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• Udelson, JE et al. Acute hemodynamic effects of conivaptan, a dual V1a and V2 vasopressin receptor Udelson, JE et al. Acute hemodynamic effects of conivaptan, a dual V1a and V2 vasopressin receptor antagonist, in antagonist, in patients with advanced heart failure. patients with advanced heart failure. CirculationCirculation 2001; 104:2417. 2001; 104:2417.

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