Vaptans:

These are nonpeptide vasopressin receptor antagonist developed for the correction of euvolemic or hypervolemic hyponatremia which increase serum sodium by binding vasopressin type 2 (V2) receptors expressed in renal collecting duct cells, thus cause excretion of water, namely aquaresis. The first successful use of a nonpeptide V2 receptor antagonist in humans was reported in 1993.¹ Several nonpeptide vasopressin receptor antagonists were developed including OPC-41061 and YM087, which subsequently became familiar to physicians with the names “tolvaptan” and “conivaptan,” respectively.^2-5

Tolvaptan:

Tolvaptan, is a selective vasopressin V2 receptor antagonist which is available for the treatment of clinically significant hypervolemic and euvolemic hyponatremia was first approved by FDA in May 22, 2009 as Samsca (Otusuka Pharmaceutical Co., Ltd.).⁶

Mechanism of Action:

Tolvaptan was thought to be clinically useful for the treatment of diseases characterized by fluid retention. Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), is a small peptide that regulates serum osmolality and blood pressure. This is a hormone synthesized in the supraoptic and paraventricular nuclei in the hypothalamus and is contained in granules which travel down the axons of the supraopticohypophyseal tract to the posterior pituitary where it is stored and subsequently released upon stimulation.⁷ AVP secretion is mediated by several mechanisms. The most sensitive stimulus for AVP release is osmotic pressure and is mediated by osmoreceptors in the hypothalamus.⁸Osmotic pressure greatly influences sodium concentration. A decrease in osmolality as minimal as 1% to 2% rapidly suppresses AVP secretion and induces aquaresis. Arterial pressure reduction also stimulates AVP release, but typically there must be a significant reduction of 10% to 20% as sensed by baroreceptors in the left atrium and aorta. It appears that arterial pressure provokes AVP release by lowering the set point of the osmoregulatory system. The effects of vasopressin are mediated through three receptor subtypes: (1) Vasopressin type 1 receptors (V₁Rs) (2) Vasopressin type 2 receptors (V₂Rs) and 3) Vasopressin type 3 receptors (V₃Rs).⁹ AVP stimulates both V_1A and V₂ receptors. V_1A receptors are located in vascular smooth muscle and cause arterial vasoconstriction to compensate for low arterial pressure. Tolvaptan has an affinity for the V2 receptor that is 1.8 times greater than that of native arginine vasopressin. Tolvaptan affinity for the V2 receptor is 29 times greater than for the V1 a receptor. AVP exerts its anti-diuretic effect by stimulating the V₂ receptor located on the basolateral side of the principal cell in the cortical collecting duct. Binding of vasopressin to V2 receptors which are located on renal collecting duct cells were competitively inhibited by Tolvaptan thus prevents vasopressin-mediated activation of these receptors and leads to an increase in the water permeability of the collecting duct causing an increase in the concentration of urine and a fall in serum sodium concentration.¹⁰ Tolvaptan is different from other conventional diuretics because it does not stimulate the sodium channel and increases free water excretion without affecting urinary sodium and potassium excretion.

Indications:

Tolvaptan in Hyponatremia:

One of the most common electrolyte irregularities recognized in one of five hospitalized patients is Hyponatremia, characterized as serum sodium concentration < 135 mEq/L.¹¹Hyponatremia is reported to be related withincreased morbidity and mortality among patientswith heart, liver or neurologic disease.^12-14 Hyponatremia not only is a marker of disease severity but also contributes to illness, even in patients with mild chronic hyponatremia, increasing the risk of falls and cognitive dysfunction.¹⁵ Acute hyponatremia is characterized by onset of symptoms <48hrs resulting from cerebral edema induced by water movement into the brain. These may include seizures, impaired mental status or coma and death. The treatment of hyponatremia is determined by the volume status of the patient, presence or absence of symptoms of hyponatremia, severity and duration of hyponatremia. Hyponatremia is the consequence of an excess of water relative to total body sodium and can be associated with increased, normal or reduced plasma osmolality. Hypotonic hyponatremia is the most frequent form encountered in clinical practice and can be classified based on extracellular volume status into hypovolemic, as observed in emesis and diarrhea, euvolemic, as seen in syndrome of inappropriate ADH secretion (SIADH) and hypervolemic forms as in heart failure and liver cirrhosis. Hypovolemic hyponatremia is treated with isotonic saline infusion. V₂ receptor antagonists have a role in management of only hypervolemic or euvolemic hyponatremia.¹⁶ The role of tolvaptan in patients with euvolemic or hypervolemic hyponatremia was assessed in SALT-1 and SALT-2 trials. These were phase-III, multicenter, randomized, double blind, placebo-controlled, multidose trials. In SALT-1 trial, 40% of the subjects in the tolvaptan group achieved a serum sodium concentration greater than 135 mEq/l at day 4 as compared to 13% in the placebo group. At day 30, 53% of the subjects in the tolvaptan group had serum sodium concentration greater than 135 mEq/l in comparison to 25% in the placebo group. Similarly, in the SALT-2 trial, the numbers were 55% and 11% at day 4 and 58% and 25% at day 30 in the tolvaptan group and placebo group respectively. However, hyponatremia recurred during the week after discontinuation of tolvaptan on day 30.¹⁷

Tolvaptan in cirrhosis:

One of the common and important complication of decompensated liver cirrhosis is hyponatremia and cirrhotic patients with hyponatremia have increased mortality.^18,19 Hyponatremia may affect brain function and lead to hepatic encephalopathy. Hyponatremia also represents a risk factor for liver transplantation as it is associated with increased occurrence of complications and impaired short-term survival after transplantation. Severe hyponatremia also complicates fluid management in cirrhosis. Salt restriction and diuretics, such as spironolactone and furosemide are used for the treatment of ascites.²⁰These treatments, however, aggravate hyponatremia and in cases of severe hyponatremia, treatment has to be suspended. In contrast, sodium replacement for severe hyponatremia predispose to fluid retention and rapid ascites accumulation. Vaptans has been shown to reverse hyponatremia in patients with syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure and cirrhosis.²¹ Hyponatremia was defined as serum sodium level < 135 mmol/L in the general population but arbitrarily as < 130 mmol/L in cirrhotic patients, according to the European Association for the Study of the Liver (EASL) guidelines because chronic asymptomatic hyponatremia is common in cirrhotic patients, particularly in the presence of ascites.^22,23

Tolvaptan could improve not only hyponatremia but also edema and ascites in patients with cirrhosis.²⁴Hepatic edema is one of the most common symptoms in patients with liver cirrhosis. The mainstays of treatment of hepatic edema include rest, dietary sodium restriction and the use of diuretics. But it may cause elevation in hyponatremia or kidney dysfunction. In a prospective cohort study conducted about the safety and utility of tolvaptan in cirrhotic patients concluded that, short-term tolvaptan treatment is safe and can improve serum sodium level in cirrhotic patients with hyponatremia. Normalization of serum sodium level is associated with better survival^.25 The SALT trials showed that tolvaptan treatment rapidly and effectively correct hyponatremia in these settings, including cirrhosis, and it has been shown that this agent can be safely and effectively used in long-term treatment.

Tolvaptan in Autosomal dominant polycystic kidney disease:

Tolvaptan was approved by FDA in April 23, 2018 as Jynarque (Otuska Pharmaceutical Co., Ltd) for the treatment of rapidly progressing Autosomal dominant polycystic kidney disease in adults. In adults, Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of end-stage kidney disease. When the genes encoding polycystin 1 (PKD1) and polycystin 2 (PKD2) are destroyed, tubular epithelial cells in vasopressin-sensitive distal nephrons and collecting ducts show enhanced proliferation, chloride-driven fluid secretion, and expression of proinflammatory cytokines, resulting in cyst development and the destruction of renal parenchyma.²⁶

Vasopressin promotes kidney-cyst cell proliferation and fluid secretion by means of up-regulation of adenosine-3′,5′-cyclic monophosphate (cAMP). The suppression of vasopressin production, release, or action by means of hydration, V₂-receptor blockade, or genetic mutation has been shown to reduce cyst burden, protect kidney function, and prolong survival in rodent models. Decreased CAMP concentrations prevent aquaporin 2 containing vesicles from fusing with the plasma membrane, which in turn causes an increase in urine water excretion, an increase in free water clearance and a decrease in urine osmolality. Tolvaptan is the first disease modifying agent for ADPKD. Tolvaptan inhibit cyst growth and slow the decline of kidney function. In a phase 3, multicenter, double blind, placebo controlled trial they found that increase in total kidney volume in the tolvaptan group was 2.8% per year versus 5.5% in the placebo group. Tolvaptan was associated with a slower decline in kidney function but was associated with a higher discontinuation rate, owing to adverse events.

Tolvaptan in Heart Failure:

Congestive heart failure (CHF) is a clinical condition with reduced cardiac output and tissue hypo-perfusion, leading to morbidity and mortality. Patients with CHF typically present with shortness of breath, fatigue, pedal edema and exercise intolerance, thereby resulting in poor quality of life, frequent hospitalization, and a shorter life expectancy. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program evaluated the effects of tolvaptan on clinical status, morbidity and mortality in patients hospitalized for Acute Heart Failure. In patients hospitalized with HF, oral tolvaptan in addition to standard therapy including diuretics improved many, though not all, HF signs and symptoms, without serious adverse events. Tolvaptan causes aquaresis, the excretion of electrolyte-free water without accompanying solutes by directly blocking binding of arginine vasopressin (AVP) to its renal receptors in patients with volume overload, potentially facilitating decongestion and improving the clinical course of patients with acute heart failure (AHF).²⁷

Tolvaptan in SIADH:

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) involves the continued secretion or action of arginine vasopressin (AVP) in contempt of normal or increased plasma volume, resulting impairment of water secretion and body retains water instead of excreting it normally in urine and produces the hyponatremia (ie, serum Na⁺ < 135mmol/L) with concomitant hypo-osmolality (serum osmolality < 280 mOsm/kg) and high urine osmolality that are the trademark of SIADH.²⁸ Short term therapy of tolvaptan remains safe and effective in hospitalized patients. It is used in patients who are unresponsive to first line therapy with fluid restriction or without prior use of demeclocycline or fluid restriction was contraindicated due to risk of dehydration and acute kidney injury.²⁹

Pharmacokinetics and metabolism:

Tolvaptan take about 2-3 hours were taken to achieve peak plasma concentration (Cmax).³⁰In patients with chronic heart failure, steady state pharmacokinetic parameters were noticed after 7 days daily administration of 30 mg of the drug (n = 20). The Cmax achieved was 283ng/mL after a median time of 2 hours (tmax) after administration. Tolvaptan has a volume of distribution nearly 3L/kg. The drug is highly protein bound (98% to 99%). Tolvaptan is metabolized principally via the cytochrome P 450 (CYP 3A) isoenzymes and is eliminated by routes other than renal that is mainly in liver. Less than 1 percent of the drug is excreted unchanged in the urine.³¹ The halflife of tolvaptan is nearly 6–8 hours. The clearance of tolvaptan is reduced to half in patients with hyponatremia of any etiology which is 4 mL/min/kg in healthy people. The mean elimination half-life of Tolvaptan was 9.4 hours after oral administration of 30mg drug once daily for 7 days in patients with New York Heart Association class II or III heart failure.³²

Predictors of tolvaptan response:

Body weight:

In a study conducted by Kawaratani et al in cirrhosis patients with ascites patients with ≥2 kg loss of BW after 7 days treatment with tolvaptan were defined as responders and those with <2 kg weight loss, or weight gain, were defined as poor responders.³³

CD14:

Serum soluble CD14 breakup as a result of inflammatory responses of lipopolysaccharides, and released from membrane-bound CD14 on peripheral blood mononuclear cells as a result SCD14 levels increases as chronic liver disease progress. Patients having higher serum CD14 had a poor response to Tolvaptan. sCD14 level ≥1665pg/ml to be a significant predictive marker of TVP efficacy.³⁴

AQP2 levels:

Decreased urine Aquaporin 2/ plasma arginine vasopressin is an important predictor of tolvaptan response in Heart failure patients.³⁵

Urine volume:

An increase in urine volume of ≥ 500mL or ≥ 2,000 mL/day of urination on the day following treatment with tolvaptan, is an important marker of tolvaptan responsiveness as described by Ohki et al.

Serum sodium level:

In cirrhotic patients with hyponatremia Sodium level in serum is increased in those who were treated with tolvaptan because of free water clearance without increasing Na elimination.³⁶

Na/K ratio:

Baseline spot urine Na/K is simple to perform and readily available and is a predictor of effective response to tolvaptan therapy. It might serve as an indicator of optimal timing of tolvaptan administration in patients with inadequate response to conventional Na diuretic therapy. A spot urine Na/K ratio greater than 2.5 prior to administration was predictive of effective tolvaptan treatment.³⁷

Adverse effects:

Hypernatremia:

Elderly patients, are at more risk of developing hypernatremia. Whatever the treatment period a low dose of tolvaptan is recommended to prevent hypernatremia. Before starting treatment with tolvaptan, it is essential to check the serum electrolyte levels.³⁸

Tolvaptan induced liver failure:

In preclinical trials tolvaptan was not found to be causing elevation of liver enzymes or liver injury. But, in a small proportion of cirrhosis patients treated with tolvaptan worsening of hepatic failure and complications of portal hypertension such as variceal hemorrhage, hepatic encephalopathy and worsening of jaundice were reported. Tolvaptan is metabolized by the microsomal P450 drug metabolizing enzyme CYP 3A4 and liver injury may be the result of conversion of tolvaptan to a toxic intermediate. In a clinically controlled trial tolvaptan [up to 120mg daily] vs placebo for 3 years in 1445 adults with polycystic kidney disease ALT elevations>2.5 times ULN occurred in 4.9% on tolvaptan vs 1.2% on placebo and 2 patients developed ALT elevations with jaundice, but no patient died and "the abnormalities either cured during treatment or returned towards baseline values after dose reduction or stopping the drug.³⁹

Others:

The most common side effects seen in the SALT-1 and SALT-2 clinical trials were thirst and dry mouth (doses used- 30mg and 60mg) in nearly 15% of the subjects in tolvaptan group. There were 26 severe adverse events noted in the SALT trials. Eleven such events occurred in eight subjects in tolvaptan group- dehydration and dizziness, dehydration and hypotension, syncope, ascites, acute renal failure, hypernatremia with increased serum creatinine and Escherichia coli septicemia with respiratory failure. 105 of the 111 subjects experienced an adverse event, in the SALTWATER trial the common ones being peripheral edema (n = 25), hyponatremia (n = 23), anemia (n = 20), diarrhea (n = 19), urinary tract infection (n = 18), nausea (n = 17), fatigue (n = 15), hypokalemia and headache (n = 14), ascites, hypotension, pneumonia (n = 13), heart failure, thirst and dizziness (n = 12). The adverse events probably related to tolvaptan therapy were polyuria (n = 11), thirst (n = 10), fatigue (n=6), dry mouth, polydipsia, polyuria, hypotension, hypernatremia, dizziness, headache, peripheral edema and acute renal failure (n=4).⁴⁰ By using 12 item short form general health survey questions and Glasgow coma scale mental and physical functioning of tolvaptan administered patients were described and the most common ADR observed were thirst, hyperkalemia, dry mouth.

Drug Interactions:

As it is metabolized by CYP3A and is an inhibitor and substrate of P-glycoprotein tolvaptan has serious drug interactions. When tolvaptan administered along with ketoconazole, an inhibitor of CYP3A, increased the exposure to tolvaptan about 5fold. As per US prescribing information. tolvaptan should not be given with ketoconazole, clarithromycin, ritonavir, indinavir, nelfinavir and nefazodone which are strong inhibitors of CYP3A. Concomitant administration of rifampicin, a CYP3A inducer decreased the exposure to tolvaptan by approximately 85%. High dosages are hence needed when used with CYP3A inducers. Increased dosage is needed when administered with a P-glycoprotein inhibitor such as cyclosporine. Simultaneous administration with digoxin (a P-glycoprotein substrate) increased the exposure to digoxin 1.3 times while when administered with warfarin, amiodarone, furosemide, hydrochlorothiazide or lovastatin there were no important changes in pharmacokinetics.

Cost Effectiveness of Tolvaptan:

A retrospective cohort analysis found that the duration of stay (LOS) in the hospital was 2 days more for patients admitted with hyponatremia, and intensive care unit admission was 10% higher for patients with moderate- to-severe hyponatremia when compared to patients without hyponatremia.⁴¹ A 15% decrease in hospital days was observed in the post hoc analysis of the EVEREST trial for hyponatremic patients treated with tolvaptan in comparison with patients received placebo.⁴² Tolvaptan was found to be a main approach compared with placebo; it was associated with decreased costs and high effectiveness over the 1-month study.

CONCLUSION:

Tolvaptan is the first orally active vasopressin receptor 2 antagonist used to treat hyponatremia, ascites, hepatic edema associated with congestive heart failure, cirrhosis and the syndrome of inappropriate antidiuretic hormone. Body weight, urine sodium potassium ratio, sCD14 levels will effectively predict response to tolvaptan.

Dry mouth, increased thirst, polyuria, hyperkalemia were the most frequently occurred side effects found in the previous studies.

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Received on 31.01.2020 Modified on 08.05.2020

Research J. Pharm. and Tech. 2021; 14(6):3455-3460.

DOI: 10.52711/0974-360X.2021.00601