Tolvaptan

Structural formula
Simplified structural formula without stereochemistry
General
Surname	Tolvaptan
other names	( RS ) - N - [4- (7-chloro-5-hydroxy-2,3,4,5-tetrahydrobenzo [ b ] azepine-1-carbonyl) -3-methylphenyl] -2-methylbenzamide ( IUPAC ) OPC-41061 (development code)
Molecular formula	C 26 H 25 ClN 2 O 3
External identifiers / databases
CAS number 150683-30-0 EC number 691-537-5 ECHA InfoCard 100.219.212 PubChem 216237 ChemSpider 187438 DrugBank DB06212 Wikidata Q426132
Drug information
ATC code	C03 XA01
properties
Molar mass	448.94 g mol −1
Physical state	firmly
Melting point	220-221 ° C
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances no GHS pictograms H and P phrases H: no H-phrases P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Tolvaptan is the international non-proprietary name for a drug used to increase the excretion of water from the body.

Tolvaptan is approved

• as Samsca for the treatment of abnormally low sodium levels in the blood ( hyponatremia ) in adults, caused by Schwartz-Bartter syndrome (SIADH), and
• as Jinarc for the treatment of adults with autosomal dominant polycystic kidney disease (PKD). This is a genetic disease in which there are numerous in the kidney fluid-filled cysts form (known as cystic kidneys ) that eventually the kidney function decrease and can lead to kidney failure.

The preparations are marketed by the Japanese pharmaceutical company Ōtsuka .

Working principle

Tolvaptan is supposed to selectively suppress the reabsorption of free water triggered by the antidiuretic hormone (ADH, also vasopressin) via aquaporins (water channels in the membrane of the cells ) in the collecting duct of the kidney ( vasopressin antagonist ). Tolvaptan binds to the arginine vasopressin receptor 2 with a factor of 1.8 higher affinity than vasopressin , which inhibits it and increases the excretion of water ( diuresis ). The elimination is not influenced by the electrolytes dissolved in the water. The principle of action of tolvaptan differs significantly in this respect from that of conventional diuretics .

Pharmacokinetics

After ingestion, tolvaptan is rapidly absorbed. The maximum concentration in the blood plasma is reached after about two hours, with about 56% of the dose being bioavailable . The plasma half-life is around eight hours. Excretion mainly takes place via the liver-bile-intestinal system. Less than 1% is eliminated with the urine via the kidney- bladder route .

Treatment of SIADH

Tolvaptan has been approved in the European Union since August 2, 2009 under the brand name Samsca for the treatment of adults with hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) . It is the first orally available V2 selective vasopressin receptor antagonist.

Tolvaptan treatment must be started at a dose of 15 mg once daily. Depending on tolerability, the dose can be increased to a maximum of 60 mg once a day in order to achieve the desired sodium level in the serum.

Side effects

In clinical trials with tolvaptan, patients were very likely to feel thirsty or sick , which means more than 1 in 10 people . Common, i.e. 1 to 10 out of 100 people treated, were dry mouth , excessive water consumption, increased urination or frequent urination, water loss, tiredness, general weakness, lack of appetite, constipation, dizziness, low blood pressure on standing up, fainting, blotchy skin bleeding, itching, fever , an increase in sodium, potassium, creatinine, uric acid and blood sugar levels, and a decrease in blood sugar levels.

In March 2012, the manufacturer Ōtsuka pointed out in a red-hand letter the risk of too rapid increases in serum sodium when using tolvaptan.

The EMA issued a warning in May 2013 that an overdose of tolvaptan could lead to liver damage.

Contraindications

Tolvaptan should be taken in the event of anuria (greatly reduced urine production), hyponatremia in the case of extracellular volume deficiency (hypovolemic hyponatremia), in the case of real volume depletion (e.g. due to diarrhea , bleeding or vomiting), in hypernatremia , in patients without a feeling of thirst, during of pregnancy and lactation , as well as a hypersensitivity to the drug or to any component of its formulation to be dispensed ( contraindications ).

Treatment of ADPKD

Jinarc is the first drug approved in Europe for adults with autosomal dominant polycystic kidney disease (ADPKD) with baseline renal failure stages 1 to 3 with signs of rapid disease progression. Tolvaptan is a selective vasopressin 2 (V ₂ ) receptor antagonist that reduces renal function loss and reduces renal cyst growth. The EU approval took place in May 2015.

The efficacy and safety of tolvaptan have been demonstrated in a clinical trial program including the international three-year, randomized, double-blind, placebo-controlled phase 3 study TEMPO 3/4 in over 1,400 adult ADPKD patients.

Selective mechanism of action

Tolvaptan specifically blocks the binding of vasopressin to the vasopressin-2 receptor (V ₂ receptor) in the tubular epithelial cells of the distal sections of the nephron. Tolvaptan's binding affinity for this receptor is 1.8 times higher than that of the body's own vasopressin.

Vasopressin (also antidiuretic hormone, ADH) regulates water retention in the body - and thus the urine concentration - by activating water reabsorption in the collecting ducts of the kidneys (antidiuresis). After vasopressin binds to the V2 receptor, the signaling pathways controlled by cyclic adenosine monophosphate (cAMP) are set in motion, which then lead to antidiuresis. Vasopressin is the main stimulus for cAMP production in the collecting duct and distal nephron.

In ADPKD, mutations in the PKD1 or PKD2 genes lead, among other things, to an upregulation of the V2 receptor and thus to overactive vasopressin signaling. The resulting increase in cAMP concentration promotes the formation and growth of cysts in the kidneys via the protein kinase A (PKA) signaling pathway.

As tolvaptan displaces vasopressin at the V ₂ receptor, cAMP production is reduced so that cell proliferation, cyst formation and growth as well as increased water excretion (aquaresis) are reduced.

Side effects and contraindications

Due to the mechanism of action of tolvaptan, which leads to an increased aquarium , the most common side effects are thirst, polyuria , nocturia and pollakiuria . Headache, dizziness , fatigue and exhaustion are other common undesirable side effects.

The TEMPO 3/4 study showed an increased risk of liver damage in ADPKD patients taking tolvaptan. Clinically meaningful elevations in the liver enzyme alanine aminotransferase were more common (4.9%) in patients receiving tolvaptan than in patients receiving placebo (1.2%).

Tolvaptan treatment must be initiated and monitored under the supervision of physicians experienced in the management of ADPKD and with full knowledge of the risks of tolvaptan therapy, including hepatotoxicity and monitoring requirements.

Tolvaptan must not be used in the case of increased liver enzyme values and pre-existing liver disease, hypersensitivity to the active ingredient, anuria , hypernatremia , hypovolemia and in people who do not feel thirsty, as well as during pregnancy and breastfeeding.

synthesis

Tolvaptan can be synthesized in several stages, for example from 3-chloro-2-nitrobenzoic acid. For this purpose, p -toluenesulfonic acid chloride (TsCl) and potassium tert -butanolate ( t -BuOK) are used.

Stereochemistry

Tolvaptan contains a stereocenter and consists of two enantiomers. This is a racemate , i.e. a 1: 1 mixture of ( R ) - and ( S ) -form:

Tolvaptan enantiomers
CAS number: 331947-66-1	CAS number: 331947-44-5

further reading

• GA Reif, T. Yamaguchi, E. Nivens, H. Fujiki, CS Pinto, DP Wallace: Tolvaptan inhibits ERK-dependent cell proliferation, Cl-secretion and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. In: American Journal of Physiology-Renal Physiology . 2011; 301: F1005-F1013. doi : 10.1152 / ajprenal.00243.2011 . PMID 21816754 .
• HD Zmily, S. Daifallah, JK Ghali: Tolvaptan, hyponatremia, and heart failure. In: International journal of nephrology and renovascular disease Volume 4, 2011, pp. 57-71, doi : 10.2147 / IJNRD.S7032 . PMID 21694950 . PMC 310879 (free full text).
• A. Ambrosy, SR Goldsmith, M. Gheorghiade: Tolvaptan for the treatment of heart failure: a review of the literature. In: Expert Opinion on Pharmacotherapy Volume 12, Number 6, April 2011, pp. 961-976, doi : 10.1517 / 14656566.2011.567267 , PMID 21401442 .
• E. Ferrer: Tolvaptan for the treatment of hyponatremia and congestive heart failure. In: Drugs of Today Volume 46, Number 3, March 2010, pp. 163-171, doi : 10.1358 / dot.2010.46.3.1464842 , PMID 20467590 .
• GL Plosker: Tolvaptan. In: Drugs . 2010; 70: p. 443–454, doi : 10.2165 / 11204630-000000000-00000 , PMID 20205486 .
• M. Gheorghiade, WA Gattis et al. a .: Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. In: Journal of the American Medical Association . 2004; 291: p. 1963-1971, doi : 10.1001 / jama.291.16.1963 , PMID 15113814 .

Individual evidence

1. ↑ A. Cordero-Vargas: Bioorganic & Medicinal Chemistry, Volume 14, No. 18, 2006, pp. 6165-6173.
2. ↑ ^{a b} Datasheet Tolvaptan from Sigma-Aldrich , accessed on May 22, 2017 ( PDF ).
3. ↑ ^{a b c} K. A. Gräfe, S. Siebenand: New on the market - Laropiprant, Plerixafor and Tolvaptan. In: Pharmazeutische Zeitung 40, 2009.
4. ↑ ^{a b c} ema.europa.eu: Summary of Product Characteristics. (PDF; 223 kB).
5. ↑ Rote-Hand-Brief about the risks of too rapid increases in serum sodium. (PDF; 583 kB) retrieved from the website of the Drugs Commission of the German Medical Association (AkdÄ).
6. ↑ Averaging EMA to Samsca. (PDF; 165 kB) Retrieved September 17, 2014.
7. ↑ ^{a b c d e f} JINARC information ^for professionals; As of September 2016 .
8. ↑ Torres VE et al. N Engl J Med. 2012; 367: 2407-2418.
9. ↑ Yamamura Y et al. J Pharmacol Exp Ther. 1998; 287 (3): 860-867.
10. ↑ Boone M, Deen P. Pflugers Arch. 2008; 456 (6): 1005-1024.
11. ↑ Gattone VH 2nd et al. Dev Genet. 1999; 24 (3-4): 309-318.
12. ↑ Belibi FA et al. Kidney Int. 2004; 66 (3): 964-973.
13. ↑ Boone M, Deen P. Pflugers Arch. 2008; 456 (6): 1005-1024.
14. ↑ Meijer E et al. Kidney Blood Press Res. 2011; 34 (4): 235-244.
15. ↑ Grantham JJ et al. Nat Rev Nephrol. 2011; 7 (10): 556-566 .
16. ↑ Takiar V, Caplan MJ. Biochim Biophys Acta. 2011; 1812 (10): 1337-1343.
17. ↑ Dell KM. Adv Chronic Kidney Dis. 2011; 18 (5): 339-347.
18. ↑ Torres VE et al. Lancet 2007; 369 (9569): 1287-1301.
19. ↑ Ibraghimov-Beskrovnaya O, Natoli TA. Trends Mol Med 2011; 17 (11): 625-633.
20. ↑ K. Kondo, H. Ogawa et al. a .: 7-chloro-5-hydroxy-1- [2-methyl-4- (2-methylbenzoyl-amino) benzoyl] -2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061) : a potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist. In: Bioorganic & Medicinal Chemistry Volume 7, Number 8, August 1999, pp. 1743-1754, PMID 10482466 .
21. ↑ Rote Liste Service GmbH (Ed.): Rote Liste 2017 - drug directory for Germany (including EU approvals and certain medical devices) . Rote Liste Service GmbH, Frankfurt / Main, 2017, edition 57, ISBN 978-3-946057-10-9 , p. 222.

Web links

• Public Assessment Report (EPAR) of the European Medicines Agency (EMA) for: Tolvaptan

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !