Tolvaptan

Tolvaptan
Clinical data
Trade names Samsca, Jinarc
Synonyms OPC-41061
AHFS/Drugs.com Monograph
MedlinePlus a609033
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration
    Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability Unknown (40% absorbed)
    Protein binding 99%
    Metabolism Hepatic (CYP3A4-mediated)[1]
    Elimination half-life 12 hours (terminal)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEMBL
    ECHA InfoCard 100.219.212
    Chemical and physical data
    Formula C26H25ClN2O3
    Molar mass 448.95 g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Tolvaptan (INN, trade names Samsca and Jinarc) is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolsama & Tolvat .

    Tolvaptan was also in fast-track clinical trials[2] for polycystic kidney disease. In a 2004 trial, tolvaptan, when administered with traditional diuretics, was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia (decreased blood levels of potassium) and without having an adverse effect on kidney function.[3] In a recently published trial (TEMPO 3:4 ClinicalTrials.gov number, NCT00428948) the study met its primary and secondary end points. Tolvaptan, when given at an average dose of 95 mg per day over a 3-year period, slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001)[4]

    Side effects

    FDA has determined that the drug Samsca (tolvaptan) should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver failure[5]

    Chemistry

    Tolvaptan is a racemate, a 1: 1 mixture of the following two enantiomers:[6]

    Enantiomers of tolvaptan

    CAS number: 331947-66-1

    CAS number: 331947-44-5

    References

    1. Shoaf S, Elizari M, Wang Z, et al. (2005). "Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias". J Cardiovasc Pharmacol Ther. 10 (3): 165–71. doi:10.1177/107424840501000304. PMID 16211205.
    2. Otsuka Maryland Research Institute, Inc.
    3. Gheorghiade M, Gattis W, O'Connor C, et al. (2004). "Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial". JAMA. 291 (16): 1963–71. doi:10.1001/jama.291.16.1963. PMID 15113814.
    4. Torres, Vicente E; Chapman, Arlene B; Devuyst, Olivier; Gansevoort, Ron T; Grantham, Jared J; Higashihara, Eiji; Perrone, Ronald D; Krasa, Holly B; Ouyang, John; Czerwiec, Frank S (2012). "Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease". New England Journal of Medicine. 367 (25): 2407. doi:10.1056/NEJMoa1205511. PMC 3760207. PMID 23121377.
    5. "U.S. Food and Drug Administration." Samsca (Tolvaptan): Drug Safety Communication. N.p., 30 Apr. 2013. Web. 1 June 2014. <http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm>
    6. Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 - Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, ISBN 978-3-946057-10-9, S. 222.

    • Gheorghiade M, Niazi I, Ouyang J, et al. (2003). "Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial". Circulation. 107 (21): 2690–6. doi:10.1161/01.CIR.0000070422.41439.04. PMID 12742979. 
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