Vasopressin Receptor Antagonists

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Vasopressin Receptor Antagonists

• Alicia Notkin
• July 17, 2007

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Outline

• Introduction
• Conivaptan
• Tolvaptan
• Lixivaptan
• Satavaptan
• Conclusion
• References

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Introduction

• SIADH AVP release is not fully suppressed as it
  would normally be in a setting of hypotonicity
• CHF arterial under-distention baroreceptor
  unloading inhibit vagal suppression of AVP (as
  well as renin catecholamines)
• Cirrhosis splanchnic vasodilatation ? arterial
  underfilling w/ non-osmotic release of AVP

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Introduction (cont.)

• Even asymptomatic patients with chronic SIADH
  may have subtle psychomotor impairments
• Association of hyponatremia w/ increased
  morbidity mortality in patients w/ liver,
  heart, or neurologic disease

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Introduction

• Traditional SIADH treatments water restriction,
  salt /- a loop diuretic, increased osmole diet,
  demeclocycline, lithium
• Difficult to treat when urine osmolality is
  particularly high
• Treat based on severity of hyponatremia (how low
  how symptomatic)

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Introduction (cont.)

• ADH receptor antagonists ? a selective water
  diuresis (Na/K excretion is not affected Na K
  loss are features of chronic SIADH)
• Urine osmolality will then decrease
• Serum Na will then increase

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Vasopressin Receptor Location Functions (KI
2006)
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Structure of the Vasopressin V2 Receptor (Brenner
Rector 2004)
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Signal Transduction Via the V2 Receptor (Brenner
Rector 2004)
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Conivaptan

• Only vasopressin receptor antagonist available in
  the U.S.
• Non-selective (V2 V1a) potential for
  splanchnic vasodilatation w/ subsequent
  hypotension or variceal bleeding b/c of V1a
  effects (so not tested in cirrhotics)
• IV formulation only b/c of potent cyt P450 3A4
  inhibition if given orally (so used only for
  inpatients)
• Approved for euvolemic hyponatremia

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Conivaptan J Clin Endo Metab 2006

• 74 euvolemic (74) or hypervolemic (26) patients
  gt/ 18 years w/ Na 115-130 mEq/l, FBG lt 275mg/dl,
  serum osm lt 290 mosm/kg H20, no volume depletion
• Excluded patients w/ uncontrolled htn or
  arrhythmias, hypotension, untreated thyroid
  abnormalities or adrenal insufficiency, CrCl lt 20
  ml/min, LFTs gt 5x normal, signs of liver disease,
  HIV, those requiring emergent treatment, those on
  meds that cause or treat SIADH
• RCT giving oral conivaptan, 40 or 80mg/d, or
  placebo, given in 2 divided doses x 5 days

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Conivaptan J Clin Endo Metab 2006

• Fluid intake limited to 2L/24 hrs
• 1 outcome change from baseline in serum Na area
  under the curve
• Statistically significant change from baseline in
  serum Na AUC w/ both doses (achieved in a
  statistically significant shorter amount of time)
• AEs HA, hypotension, nausea, constipation
• Aquaretic effects persisted for at least 6hrs

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Tolvaptan

• Not yet available in the U.S.
• V2 selective blocks binding of arginine
  vasopressin to the V2 receptors of the distal
  nephron only
• Oral

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Tolvaptan NEJM 2006

• Report of 2 RCT SALT-1 SALT-2 (Study of
  Ascending Levels of Tolvaptan in Hyponatremia)
• Euvolemic or hypervolemic patients gt 18 years w/
  Na lt 135 mmol/L either chronic heart failure,
  cirrhosis, or SIADH mostly outpatients
• Excluded patients w/ psychogenic polydipsia, head
  trauma, postop conditions, uncontrolled
  hypothyroidism or adrenal insufficiency, or
  medication-induced hyponatremia

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Tolvaptan NEJM 2006

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

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Tolvaptan NEJM 2006

• 223 given placebo, 225 given tolvaptan
• Initial dose 15mg qd, titrated to max of 60
  based on serum Na
• Primary endpoints change in the average daily
  area under the curve for serum Na from baseline
  to day 4 baseline to day 30

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Baseline Characteristics
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(No Transcript)
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Tolvaptan NEJM 2006

• Increase in average daily AUC for serum Na was
  significantly greater in the tolvaptan group
• Also seemed to be improvement in self-assessed
  mental component summary score
• Dry mouth, thirst, as well as constipation,
  weakness, hyperglycemia, urinary frequency were
  seen more in the tolvaptan group

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Lixivaptan

• Not yet available in the U.S.
• V2 selective
• Oral
• Gastroenterology 2003 RCT of 66 patients w/
  cirrhosis hyponatremia (no SIADH or CHF)
  assigned to 100 or 200mg/d of lixivaptan or
  placebo, plus 1L fluid restriction, until Na gt/
  136 or 7 days

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Lixivaptan (cont.)

• Statistically significant difference in the of
  patients achieving a normal serum Na compared to
  placebo
• Significant reduction in Uosm body weight
• Significant increase in thirst in the high dose
  group

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Lixivaptan (cont.)

• Hepatology 2003 44 hospitalized patients w/ Na
  lt 130 mmol/L (5 w/ SIADH, 33 w/ cirrhosis, 6 w/
  CHF), given 25, 125, or 250mg 2x/d or placebo
  doses held for excessive Na rise, dehydration,
  encephalopathy
• Significant response (increased water clearance
  and serum Na) compared to placebo significant
  dose related increase in Na
• Higher doses ? significant dehydration

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Satavaptan

• Not yet available in the U.S.
• V2 selective
• Oral
• CJASN 2006 34 patients treated w/ satavaptan
  25mg, 50mg, or placebo x 5 days ? 23 days of
  open-label dosage-adjustment period
• Statistically significant response in treatment
  group re. Na normalization or increase by gt/
  5mmol/L

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Conclusion

• Vasopressin receptor antagonists can cause an
  electrolyte-free aquaresis, reduce urine
  osmolality, raise serum Na
• Risk of overly rapid correction of hyponatremia
  seems low
• Main side effect is increased thirst
• Tachyphylaxis does not seem to occur

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Conclusion (cont.)

• Possibility of hypotension variceal bleeding in
  cirrhotics if given a V1aR blocker
• ? Bleeding complications from V2R inhibition in
  vascular endothelium
• ? Role in CHF mortality data conflicting
• v. benefit

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Conclusion (cont.)

• PCKD polycystin defects may promote cyst
  development b/c they ? increases in intracellular
  cAMP (a second messenger for AVP acting at the
  V2R) therefore, V2R antagonists may ? reduced
  cyst volume
• Congenital NDI type 2 V2R mutations cause
  misfolding interfere w/ trafficking of the
  receptor from the ER to the cell membrane VRA
  can bind to misfolded intracellular V2R improve
  transport to the cell membrane

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References

• Abraham, WT et al. Aquaretic effect of
  lixivaptan, an oral, non-peptide, selective V2
  receptor vasopressin antagonist, in New York
  Heart Association functional class II and III
  chronic heart failure patients. JACC 2006
  47(8)1615.
• Gerbes, AL et al. Therapy of hyponatremia in
  cirrhosis with a vasopressin receptor antagonist
  a randomized double- blind multicenter trial.
  Gastroenterology 2003 124933.
• Ghali, JK et al. Efficacy and safety of oral
  conivaptan a V1a/V2 vasopressin receptor
  antagonist, assessed in a randomized,
  placebo-controlled trial in patients with
  euvolemic or hypervolemic hyponatremia. J Clin
  Endo Metab 2006 2145.
• Gheorghiade, M et al. Effects of tolvaptan, a
  vasopressor antagonist, in patients hospitalized
  with worsening heart failure a randomized
  controlled trial. JAMA 2004 2911963.
• Gheorghiade, M et al. Vasopressin V2-receptor
  blockade with tolvaptan in patients with chronic
  heart failure results from a double-blind,
  randomized trial. Circulation 2003 1072690.
• Konstam, MA et al. Effects of oral tolvaptan in
  patients hospitalized for worsening heart
  failure the EVEREST outcome trial. JAMA 2007
  2971319.
• Renneboog, B et al. Mild chronic hyponatremia is
  associated with falls, unsteadiness, and
  attention deficits. Am J Med 2006 11971.
• Schrier, RW et al. Tolvaptan, a selective oral
  vasopressin V2-receptor antagonist, for
  hyponatremia. NEJM 2006 3552099.
• Soupart, A et al. Successful long-term treatment
  of hyponatremia in syndrome of inappropriate
  antidiuretic hormone secretion with satavaptan
  (ST121463B), an orally active nonpeptide
  vasopressin V2-receptor antagonist. Clin J Am
  Soc Nephrol 2006 11154.
• Udelson, JE et al. Acute hemodynamic effects of
  conivaptan, a dual V1a and V2 vasopressin
  receptor antagonist, in patients with advanced
  heart failure. Circulation 2001 1042417.
• Verbalis, JG. Pathogenesis of hyponatremia in an
  experimental model of the syndrome of
  inappropriate antidiuresis. Am J Physiol 1994
  267R1617.
• Verbalis, JG et al. Vasopressin receptor
  antagonists. KI 2006 692124.
• Wong, F et al. A vasopressin receptor antagonist
  (VPA-985) improves serum sodium concentration in
  patients with hyponatremia a multicenter,
  randomized, placebo-controlled trial. Hepatology
  2003 37(1)182.
• www.uptodate.com

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The End