Vasopressin Receptor Antagonists Alicia Notkin July 17, 2007

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Text of Vasopressin Receptor Antagonists Alicia Notkin July 17, 2007

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  • Vasopressin Receptor Antagonists Alicia Notkin July 17, 2007
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  • Outline Introduction Introduction Conivaptan Conivaptan Tolvaptan Tolvaptan Lixivaptan Lixivaptan Satavaptan Satavaptan Conclusion Conclusion References References
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  • Introduction SIADH AVP release is not fully suppressed as it would normally be in a setting of hypotonicity 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) 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 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 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 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 Traditional SIADH treatments: water restriction, salt +/- a loop diuretic, increased osmole diet, demeclocycline, lithium Difficult to treat when urine osmolality is particularly high Difficult to treat when urine osmolality is particularly high Treat based on severity of hyponatremia (how low & how symptomatic) 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) 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 Urine osmolality will then decrease Serum Na will then increase 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. 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) 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) IV formulation only b/c of potent cyt P450 3A4 inhibition if given orally (so used only for inpatients) Approved for euvolemic hyponatremia Approved for euvolemic hyponatremia
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  • Conivaptan J Clin Endo Metab 2006 74 euvolemic (74%) or hypervolemic (26%) patients >/= 18 years w/ Na 115-130 mEq/l, FBG /= 18 years w/ Na 115-130 mEq/l, FBG < 275mg/dl, serum osm < 290 mosm/kg H20, no volume depletion Excluded patients w/ uncontrolled htn or arrhythmias, hypotension, untreated thyroid abnormalities or adrenal insufficiency, CrCl 5x normal, signs of liver disease, HIV, those requiring emergent treatment, those on meds that cause or treat SIADH Excluded patients w/ uncontrolled htn or arrhythmias, hypotension, untreated thyroid abnormalities or adrenal insufficiency, CrCl 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 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 Fluid intake limited to 2L/24 hrs 1* outcome: change from baseline in serum Na area under the curve 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) 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 AEs: HA, hypotension, nausea, constipation Aquaretic effects persisted for at least 6hrs Aquaretic effects persisted for at least 6hrs
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  • Tolvaptan Not yet available in the U.S. Not yet available in the U.S. V2 selective: blocks binding of arginine vasopressin to the V2 receptors of the distal nephron only V2 selective: blocks binding of arginine vasopressin to the V2 receptors of the distal nephron only Oral Oral
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  • Tolvaptan NEJM 2006 Report of 2 RCT: SALT-1 & SALT-2 (Study of Ascending Levels of Tolvaptan in Hyponatremia) Report of 2 RCT: SALT-1 & SALT-2 (Study of Ascending Levels of Tolvaptan in Hyponatremia) Euvolemic or hypervolemic patients > 18 years w/ Na 18 years w/ Na < 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 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 3.5 mg/dl, Child-Pugh score > 10 (unless exception), Na 3.5 mg/dl, Child-Pugh score > 10 (unless exception), Na < 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 223 given placebo, 225 given tolvaptan Initial dose: 15mg qd, titrated to max of 60 based on serum Na 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 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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  • Tolvaptan NEJM 2006 Increase in average daily AUC for serum Na was significantly greater in the tolvaptan group 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 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 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. Not yet available in the U.S. V2 selective V2 selective Oral 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 >/= 136 or 7 days 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 >/= 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 Statistically significant difference in the # of patients achieving a normal serum Na compared to placebo Significant reduction in Uosm & body weight Significant reduction in Uosm & body weight Significant increase in thirst in the high dose group Significant increase in thirst in the high dose group
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  • Lixivaptan (cont.) Hepatology 2003 44 hospitalized patients w/ Na < 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 Hepatology 2003 44 hospitalized patients w/ Na < 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 Significant response (increased water clearance and serum Na) compared to placebo; significant dose related increase in Na Higher doses significant dehydration Higher doses significant dehydration
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  • Satavaptan Not yet available in the