Overview:
Tolvaptan is a selective arginine vasopressin V2 receptor antagonist used to treat rapidly progressive cases of polycystic kidney disease. It is also used to treat hyponatremia (low sodium in the blood) in cases of heart failure or syndrome of irregular antidiuretic hormone.
Uses of Tolvaptan
Tolvaptan is a selective vasopressin V2 receptor antagonist that delays the increased kidney volume, delays the decline in renal function, and reduces pain in cases of ADPKD (autosomal dominant polycystic kidney disease). Tolvaptan binds to V2R expressed by the distal part of the nephrons with greater affinity than vasopressin. Initially, the drug was developed to induce a free water excretion in patients with diluted hyponatremia and patients with heart failure.
Contraindications of Tolvaptan (Jynarque):
Jynarque or Tolvaptan is contraindicated in patients with the following conditions:
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Unable to respond or sense the feeling of thirst.
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Hypovolemia: refers to the reduction in the liquid portion of the blood plasma after sodium or water loss from the body.
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Under the administration of CYP3A inhibitors such as grapefruit juice, ketoconazole, or verapamil.
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Hypersensitivity to any active or inactive ingredient of the drug.
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With a history of liver impairment or injury.
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Abnormal sodium concentration in the body.
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Urinary outflow complications or anuria (unable to pass urine).
For Patients:
What Is Polycystic Kidney Disease?
It is a disease that leads to numerous cysts’ growth in the kidneys. The cysts are filled with fluid. Overgrowth and an excessive number of these cysts can damage the kidney gradually. The cyst replaces the tissue of the kidney and reduces its functional capacity leading to kidney failure.
How Does Polycystic Kidney Disease Affect Other Organs?
The disease can affect other organs along with the kidney. The cysts can develop in the liver, spleen, pancreas, large intestine, or ovaries. If the polycystic kidney disease affects the brain, it can cause an aneurysm. An aneurysm is a bulging blood vessel that can burst and result in a stroke or death. If the disease affects the heart, it makes the valves floppy, which can lead to heart murmurs (sounds from the heart).
Signs and Symptoms of Polycystic Kidney Disease:
The onset of symptoms is generally very slow in cases of polycystic kidney disease. People may develop symptoms in their late 30s and 40s. The first appearing symptoms are generally:
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Increase in the size of the abdomen due to the growing size and number of cysts.
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Presence of blood in the urine.
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Pain in the back or sides of the body.
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Frequent infections in the kidney and bladder.
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Increase in blood pressure.
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Pounding or fluttering in the chest: almost 25 % of patients with polycystic kidney disease may have a floppy valve in the heart and may experience fluttering. The symptoms may disappear on their own.
What Are Different Types of Polycystic Kidney Diseases?
- Autosomal Dominant Polycystic Kidney Disease: This type of polycystic kidney disease is transferred to the child from parents by dominant inheritance. Only one copy of an abnormal gene is needed to cause the disease. It is the most common type of polycystic kidney disease. Almost 90 % of cases of cystic kidney disease are autosomal dominant.
- Infantile or Autosomal Recessive Polycystic Kidney Disease: This form of the disease can be passed from parent to child recessively. The onset of symptoms can be very early, even in the womb of life. It progresses rapidly and is often fatal in the early months of life. It is a very rare form of polycystic kidney disease.
- Acquired Cystic Kidney Disease: This form of polycystic kidney disease occurs in cases of long-term kidney damage and severe scarring often associated with kidney failure and dialysis. The majority of cases on dialysis for five years or more develop acquired cystic kidney disease.
Treatment for Polycystic Kidney Disease:
The cure for polycystic kidney disease is very questionable. However, it is suggested that drinking plain water regularly throughout the day and avoiding caffeine consumption can reduce the growth of cysts in the kidney.
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Tolvaptan is used as a medicine to control the growth of cysts and pain in cases of cystic kidney diseases.
Some other precautions which should be taken are:
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Careful control and evaluation of blood pressure.
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Healthy lifestyle without smoking and proper exercise and weight control.
More About the Drug:
Before Starting the Drug:
There are a few conditions and medications which should be mentioned to the doctor before starting the Tolvaptan drug as it can cause some severe reactions.
Some of the medications which can show unwanted interactions with Tolvaptan are:
Nefazodone: It is an antidepressant used to treat major depressive disorders.
Antibiotics such as Telithromycin (used to treat lung infection known as community-acquired pneumonia) and Clarithromycin (used to treat bacterial infections affecting the skin and respiratory system).
Antifungal drugs such as Itraconazole or Ketoconazole are used to treat fungal infections in the body.
Medical conditions which should be mentioned before starting treatment with Tolvaptan are:
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Liver problems and diseases.
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Allergies.
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Consumption of excessive amounts of alcohol.
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Cases of malnourishment.
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Breastfeeding.
How Does Tolvaptan Affect Polycystic Kidney Disease?
Tolvaptan is a selective vasopressin V2 receptor antagonist; it counters the function of vasopressin receptors and slows down kidney function decline in cases of autosomal dominant polycystic kidney disease. It lowers the intracellular cAMP (cyclic adenosine monophosphate) and inhibits fluid secretion and cell proliferation.
Conditions in Which Tolvaptan Should Be Avoided:
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If the patient has a history of liver problems or still has symptoms of liver diseases other than polycystic liver disease.
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When the individual does not feel thirsty due to dehydration.
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Cannot consume enough fluid by drinking.
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If the amount of sodium in the blood is diagnosed too low or too high.
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Allergic to Tolvaptan or any of the ingredients of the drug Jynarque.
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Difficulty in passing urine.
While Taking the Drug:
How to Take Tolvaptan Drug?
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Before taking the drug Tolvaptan, all the instructions mentioned on the prescription and medicine guidance sheet should be read properly.
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Medicine should be consumed exactly as the dose is prescribed, as any carelessness can lead to side effects or complications.
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Many fluids (especially water) should be consumed while taking Tolvaptan as dehydration can occur. Grapefruit juice or alcoholic drinks should be avoided.
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Tolvaptan can be consumed before meals or even after meals. There are no specific instructions.
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As there is dehydration after consumption of Tolvaptan, there can be other serious conditions such as vomiting, diarrhea, or sweating.
What Happens if a Dose Is Missed?
If any dose of Tolvaptan (Jynarque) is missed, the next dose should be consumed at the regular time. However, two doses should not be taken at one time.
Side Effects of Tolvaptan:
There can be the presence of any of the followings signs as a side effect of the drug:
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Irregular heartbeat and heart murmurs.
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Confusion, weakness, or light-headedness.
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Sudden weight loss.
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Symptoms of dehydration thirst, increased sweating, dry skin, and inability to urinate at normal frequency.
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Symptoms related to the liver include pain in the upper right side of the stomach, fever, itching, pallor of the skin or eyes, and loss of appetite.
Dosage of Tolvaptan:
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Jynarque is available in 15 mg, 30 mg, 45 mg, 60 mg, and 90 mg doses tablets.
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The initial dose of Jynarque is 45 mg at first, followed by 15 mg after 8 hours (total of 60 mg/day).
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Titration is done to 60 mg plus 30 mg and then to 90 mg plus 30 mg per day depending on tolerating capacity. There should be at least a week interval between the titrations.
Dose Modifications if CYP3A Inhibitors Advised:
The dose of Jynarque should be reduced if administered along with CYP3A therapy should be interrupted for a temporary duration.
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Taking 90 mg and 30 mg should be reduced to 45 mg and 15 mg.
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Consuming 60 mg and 30 mg should be reduced to 30 mg and 15 mg.
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Consuming 45 mg and 15 mg should be reduced to 15 mg and 15 mg.
If the recommended reduced doses of Jynarque are not available, the CYP3A therapy should be interrupted for a temporary duration.
For Doctors:
Indications: Tolvaptan is indicated in cases of polycystic kidney disease to slow down the kidney function decline in adults.
Mechanism of Action: Tolvaptan being a selective vasopressin two receptor antagonist, has an affinity for the V2 receptor 1.8 times more than native arginine vasopressin. The decreased binding of vasopressin to the V2 receptor in the kidney reduces adenylate cyclase activity which results in a decrease in intracellular adenosine 3’, 5’- cyclic monophosphate (cAMP) concentrations. A decrease in cAMP concentration stops aquaporin 2 containing vesicles from fusing with the plasma membrane, thus causing an increase in urine water excretion, a decrease in urine osmolarity, and an increase in the water clearance.
Pharmacodynamics:
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In the cases of healthy patients with eGFR (estimated Glomerular Filtration Rate) as low as 10 ml/min/1.73 meter square, a single dose of Tolvaptan shows aquaretic effects within 1 hour to 2 hours after the dose.
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In healthy subjects, a single dose of 60 mg and 90 mg can produce an extreme effect of a 9 ml/min increase in excretion of urine within 4-8 hours of post-dose. Increasing the dose of Tolvaptan does not increase the peak effect in excretion of urine but can sustain the effect for a prolonged duration of time.
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Changes in free water affect the changes in urine excretion rate. Free water increment leads to an increase in serum sodium concentration which remains so until the fluid intake is increased to match urine output.
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During Tolvaptan administration, there are small changes in renal function, which are independent of baseline renal function. The glomerular filtration rate is reduced by about 6 % to 10 %, and uric acid clearance is decreased to about 20 % to 25 %. The changes are reversible after the withdrawal of tolvaptan.
Pharmacokinetics of Tolvaptan
The absorption, distribution, metabolism and, elimination of tolvaptan are explained under pharmacokinetics:
Absorption: The peak concentration of Tolvaptan gets observed between 2 to 4 hours after administration of the drug. The peak concentration increases less than dose-proportional with doses more than 240 mg. The bioavailability of Tolvaptan decreases gradually with increased doses. The ideal bioavailability of Tolvaptan after an oral 30 mg dose is 56 % (range from 42 % to 80 %).
NOTE: Administration of 90 mg Jynarque with a high-fat meal with almost 50 % of food as fat doubles the peak concentration but, Tolvaptan can be administered with or without food.
Distribution: Tolvaptan binds to both alpha-1 acid glycoprotein and albumin. The overall protein binding is more than 98 %. When Tolvaptan is administered once- daily 300 mg dose or as a split dose to patients with acquired dominant polycystic kidney disease, its accumulation factor is less than 1.2.
Metabolism: Tolvaptan can be metabolized completely by CYP3A. Intravenously the half-life of Tolvaptan is approximately 3 hours, whereas, in the case of oral doses, the half-life increases from 3 hours for a 15 mg dose to almost 12 hours for 120 mg or higher doses. This happens due to the longer absorption of drugs at higher doses.
Elimination: The clearance of Tolvaptan is at approximately 4 ml/min/kg and does not get affected by increasing the dose of the drug.
Drug Interactions of Tolvaptan:
Impact of other drugs on Tolvaptan:
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Strong CYP3A Inhibitors: The Cmax and AUC of Tolvaptan were 3.5 times and 5.4 times higher following Ketoconazole (200 mg) one day prior and then along with Tolvaptan 30 mg.
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Moderate CYP3A4 Inhibitors:
- Administration of Fluconazole 400 mg one day prior and then 200 mg concomitantly showed 80 % and 200 % increase in Cmax and AUC of Tolvaptan, respectively.
- Grapefruit juice: Tolvaptan (60 mg) was taken with 240 ml of regular concentrated grapefruit juice. The Cmax and AUC increased by 90 % and 60 %, respectively.
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CYP3A Inducers: Rifampin once daily (600mg) for seven days followed by a single dose of 240 mg Tolvaptan decreases the efficacy of Tolvaptan by 85 %.
Impact of Tolvaptan on Other Drugs:
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CYP3A Substrates: Administration of Tolvaptan with Lovastatin increases the AUC of Lovastatin and its metabolite by 40 % and 30 % respectively.
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P-gp Substrates: Administration of 0.25 mg digoxin once daily for 12 days followed by co-administration of Tolvaptan from day 8 to 12 increased the Cmax and AUC of the drug by 30 % and 20 %, respectively.
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Co-administration with Furosemide, Warfarin, Hydrochlorothiazide, or Amiodarone with Tolvaptan does not alter the pharmacokinetics of these drugs.
What Are the Ingredients of Jynarque?
The active ingredient is Tolvaptan, and the inactive ingredients are hydroxypropyl cellulose, corn starch, low substituted hydroxypropyl cellulose, magnesium stearate, lactose monohydrate, and microcrystalline cellulose.
Overdose of Tolvaptan:
A single dose of 400 mg (4 times the maximum recommended daily dose) or multiple doses up to 300 mg once daily for five days are the maximum dose tolerated by the body.
In overdose cases, the elevation of vital signs, ECG, electrolyte concentrations, and fluid status is recommended. There should be continuous replacement of water and electrolytes until the normal stability is achieved. Dialysis can not be considered effective in removing tolvaptan because of its high binding affinity to plasma protein.
Clinical Trials:
The study is done to determine the efficacy of tolvaptan for treating late-stage autosomal dominant polycystic kidney diseases. The protocol will help understand the safety and efficacy of the drug Tolvaptan in autosomal dominant polycystic kidney disease patients with late stage 2 to early stage four chronic kidney disease. The trials of Tolvaptan will be compared with placebo to estimate the glomerular filtration rate (GFR) from the pre-treatment phase to post-treatment follow-ups.
Tolvaptan in Pregnancy: There is no such study or data available which can predict the effect of Tolvaptan on pregnant women. In embryo-fetal development studies of rats and rabbits who were pregnant, oral Tolvaptan showed no developmental toxicity.
Tolvaptan in Breastfeeding Mothers: No data showed the presence of Tolvaptan in human milk or any effect on breastfeeding babies. However, Tolvaptan was noticed in rat milk. When a drug is present in animal milk, there are chances for the drug to be present in human milk as well but in varying traces. Henceforth, considering the drug's complications, such as liver toxicity, electrolyte imbalances, and hypotension, it is advised to avoid breastfeeding during treatment with Tolvaptan.
Tolvaptan in Geriatric Patients: Studies did not show any specific differences in response to Tolvaptan in older patients compared to younger patients. However, dose selection for an elderly patient should be made safely, usually at low doses.
