Lesinurad

Last updated

Lesinurad
Lesinurad.svg
Lesinurad ball-and-stick model.png
Clinical data
Pronunciation /lɛˈsɪnjuːræd/
le-SIN-ew-rad
Trade names Zurampic
AHFS/Drugs.com Monograph
MedlinePlus a616015
License data
Routes of
administration 		Oral (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability ~100% [2]
Protein binding >98%
Metabolism Hepatic (CYP2C9)
Elimination half-life ~5 hours
Excretion Urine (63%), feces (32%)
Identifiers
  • 2-{[5-Bromo-4-(4-cyclopropyl-1-naphthyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ECHA InfoCard 100.216.089 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H14BrN3O2S
Molar mass 404.28 g·mol−1
3D model (JSmol)
  • c1ccc2c(c1)c(ccc2n3c(nnc3Br)SCC(=O)O)C4CC4
  • InChI=1S/C17H14BrN3O2S/c18-16-19-20-17(24-9-15(22)23)21(16)14-8-7-11(10-5-6-10)12-3-1-2-4-13(12)14/h1-4,7-8,10H,5-6,9H2,(H,22,23)
  • Key:FGQFOYHRJSUHMR-UHFFFAOYSA-N

Lesinurad (brand name Zurampic) is a urate transporter inhibitor for treating high blood uric acid levels associated with gout. [2] It is recommended only as an adjuvant with either allopurinol or febuxostat when these medications are not sufficient. [3]

Contents

It received FDA approval on 22 December 2015. [3] The European Commission granted a marketing authorisation valid throughout the European Union on 18 February 2016. [4] In February 2019, lesinurad was discontinued in the United States by its manufacturer for business reasons, and was subsequently withdrawn in Europe in July 2020. [5] [6]

Medical uses

Lesinurad is used in combination with a xanthine oxidase inhibitor, such as allopurinol or febuxostat, for treating hyperuricemia (high levels of uric acid in the blood serum) associated with gout. It is approved only for patients who have not achieved target uric acid levels with a xanthine oxidase inhibitor alone. [2]

Contraindications

The drug is contraindicated in people with tumour lysis syndrome or Lesch–Nyhan syndrome (juvenile gout), as well as severe impairment of kidney function, including kidney transplant and hemodialysis patients. [7] [8]

Adverse drug reactions

In clinical trials, serum creatinine (an important marker for kidney function) was elevated in 4.3 to 7.8% of patients depending on the dose, as compared to 2.3% under placebo. Manifest kidney problems were less frequent under the standard dose than under placebo: Kidney failure occurred in 2.1% of placebo patients, in 1.2% of patients with the therapeutic standard dose, and in 3.5% of patients with the double dose. For kidney stones, the frequencies were 1.7%, 0.6% and 2.5%, respectively. [7] [8]

Other common side effects were influenza (5.1% vs. 2.7% under placebo), headache (5.3% vs. 4.1%), and gastroesophageal reflux disease (2.7% vs. 0.8%). Hypersensitivity reactions were rare (<0.1%). [7] [8]

Interactions

The substance is a mild inducer of the liver enzyme CYP3A4. Some drugs that are metabolized by this enzyme have been shown to be slightly less effective when combined with lesinurad, examples including simvastatin and warfarin. It might also be a mild inducer of CYP2B6. On the other hand, lesinurad concentrations in the blood are decreased by drugs that induce CYP2C9 and increased by substances that inhibit this enzyme (such as fluconazole), as well as in people who have genetically determined low CYP2C9 activity. The same may be true of microsomal epoxide hydrolase inhibitors (such as valproic acid). [7]

High dose aspirin and related drugs reduce the effectiveness of other anti-gout medications. It is not known conclusively whether this also applies to lesinurad, but low dose aspirin does not negatively affect its activity. [7] [8]

Pharmacology

Mechanism of action

Lesinurad inhibits URAT1, a protein that is responsible for reabsorption of uric acid in the kidneys. This leads to increased uric acid excretion with the urine, and consequently lower blood levels. It also inhibits the protein OAT4, which is associated with hyperuricemia caused by diuretic drugs. [7] [8]

Pharmacokinetics

The main metabolic pathways in humans. Involved enzymes are 2C9 = CYP2C9 and mEH = microsomal epoxide hydrolase. Lesinurad mechanism.svg
The main metabolic pathways in humans. Involved enzymes are 2C9 = CYP2C9 and mEH = microsomal epoxide hydrolase.

Lesinurad is quickly and practically completely absorbed from the gut. Highest blood plasma concentrations are reached after one to four hours. When in the bloodstream, the substance is almost completely (>98%) bound to plasma proteins, mainly albumin. [7] [8]

It is metabolized mainly by the liver enzyme CYP2C9 to various oxidation products, predominantly to a hydroxylated substance called M3 and an epoxide, M3c. The latter is quickly hydrolyzed to the diol M4 by microsomal epoxide hydrolase (mEH). The enzymes CYP1A1, CYP2C19 and CYP3A only play minor roles in its metabolization. Glucuronidation by the enzymes UGT1A1 and UGT2B7 has also been detected. [9]

Lesinurad is excreted via the urine (63%) and feces (32%), with a biological half-life of about five hours. Of the excreted dose, 30% are unchanged lesinurad, and the rest are metabolites. [7] [8]

Pharmacogenomics

People who are CYP2C9 poor metabolizers are exposed to lesinurad concentrations that are about 1.8-fold higher than those with a normal function of this enzyme. [7] [8]

Chemistry

Two atropisomers of lesinurad. Lesinurad atropisomers.svg
Two atropisomers of lesinurad.

Lesinurad is a white to off-white powder and is not hygroscopic. It is a 1:1 racemic mixture of atropisomers. [11]

See also

Related Research Articles

<span class="mw-page-title-main">Uric acid</span> Organic compound

Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of purine nucleotides, and it is a normal component of urine. High blood concentrations of uric acid can lead to gout and are associated with other medical conditions, including diabetes and the formation of ammonium acid urate kidney stones.

<span class="mw-page-title-main">Gout</span> Form of arthritis causing swollen joints

Gout is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crystals. Pain typically comes on rapidly, reaching maximal intensity in less than 12 hours. The joint at the base of the big toe is affected (Podagra) in about half of cases. It may also result in tophi, kidney stones, or kidney damage.

<span class="mw-page-title-main">Allopurinol</span> Medication

Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken orally or intravenously.

<span class="mw-page-title-main">Hyperuricemia</span> Medical condition

Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7 mg/dL for men, and 5.5 mg/dL for youth are defined as hyperuricemia. The amount of urate in the body depends on the balance between the amount of purines eaten in food, the amount of urate synthesised within the body, and the amount of urate that is excreted in urine or through the gastrointestinal tract. Hyperuricemia may be the result of increased production of uric acid, decreased excretion of uric acid, or both increased production and reduced excretion.

<span class="mw-page-title-main">Clopidogrel</span> Antiplatelet medication

Clopidogrel—sold under the brand names Plavix and Deplat, among others—is an antiplatelet medication used to reduce the risk of heart disease and stroke in those at high risk. It is also used together with aspirin in heart attacks and following the placement of a coronary artery stent. It is taken by mouth. Its effect starts about two hours after intake and lasts for five days.

<span class="mw-page-title-main">Lesch–Nyhan syndrome</span> Rare genetic disorder

Lesch–Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This deficiency occurs due to mutations in the HPRT1 gene located on the X chromosome. LNS affects about 1 in 380,000 live births. The disorder was first recognized and clinically characterized by American medical student Michael Lesch and his mentor, pediatrician William Nyhan, at Johns Hopkins.

<span class="mw-page-title-main">Rasburicase</span> Pharmaceutical drug

Rasburicase is a medication that helps to clear uric acid from the blood. It is a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Urate oxidase is known to be present in many mammals but does not naturally occur in humans. Rasburicase is produced by a genetically modified Saccharomyces cerevisiae strain. The complementary DNA (cDNA) coding for rasburicase was cloned from a strain of Aspergillus flavus.

Uricosuric medications (drugs) are substances that increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. In general, this effect is achieved by action on the proximal tubule of the kidney. Drugs that reduce blood uric acid are not all uricosurics; blood uric acid can be reduced by other mechanisms.

<span class="mw-page-title-main">Probenecid</span> Chemical compound

Probenecid, also sold under the brand name Probalan, is a medication that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.

The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of Cytochrome P450 enzymes termed cytochrome P450 epoxygenases. These nonclassic eicosanoids are generally short-lived, being rapidly converted from epoxides to less active or inactive dihydroxy-eicosatrienoic acids (diHETrEs) by a widely distributed cellular enzyme, Soluble epoxide hydrolase (sEH), also termed Epoxide hydrolase 2. The EETs consequently function as transiently acting, short-range hormones; that is, they work locally to regulate the function of the cells that produce them or of nearby cells. The EETs have been most studied in animal models where they show the ability to lower blood pressure possibly by a) stimulating arterial vasorelaxation and b) inhibiting the kidney's retention of salts and water to decrease intravascular blood volume. In these models, EETs prevent arterial occlusive diseases such as heart attacks and brain strokes not only by their anti-hypertension action but possibly also by their anti-inflammatory effects on blood vessels, their inhibition of platelet activation and thereby blood clotting, and/or their promotion of pro-fibrinolytic removal of blood clots. With respect to their effects on the heart, the EETs are often termed cardio-protective. Beyond these cardiovascular actions that may prevent various cardiovascular diseases, studies have implicated the EETs in the pathological growth of certain types of cancer and in the physiological and possibly pathological perception of neuropathic pain. While studies to date imply that the EETs, EET-forming epoxygenases, and EET-inactivating sEH can be manipulated to control a wide range of human diseases, clinical studies have yet to prove this. Determination of the role of the EETS in human diseases is made particularly difficult because of the large number of EET-forming epoxygenases, large number of epoxygenase substrates other than arachidonic acid, and the large number of activities, some of which may be pathological or injurious, that the EETs possess.

<span class="mw-page-title-main">CYP2C9</span> Enzyme protein

Cytochrome P450 family 2 subfamily C member 9 is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the protein is encoded by the CYP2C9 gene. The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.

<span class="mw-page-title-main">Phenprocoumon</span> Drug

Phenprocoumon is a long-acting blood thinner drug to be taken by mouth, and a derivative of coumarin. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) by blocking synthesis of coagulation factors II, VII, IX and X. It is used for the prophylaxis and treatment of thromboembolic disorders such as heart attacks and pulmonary (lung) embolism. The most common adverse effect is bleeding. The drug interacts with a large number of other medications, including aspirin and St John's Wort. It is the standard coumarin used in Germany, Austria, and other European countries.

<span class="mw-page-title-main">Febuxostat</span> Chemical compound

Febuxostat, sold under the brand names Uloric among others, is a medication used long-term to treat gout due to high uric acid levels. It is generally recommended only for people who cannot take allopurinol. When initially started, medications such as NSAIDs are often recommended to prevent gout flares. It is taken by mouth.

<span class="mw-page-title-main">Hyperuricosuria</span> Medical condition

Hyperuricosuria is a medical term referring to the presence of excessive amounts of uric acid in the urine. For men this is at a rate greater than 800 mg/day, and for women, 750 mg/day. Notable direct causes of hyperuricosuria are dissolution of uric acid crystals in the kidneys or urinary bladder, and hyperuricemia. Notable indirect causes include uricosuric drugs, rapid breakdown of bodily tissues containing large quantities of DNA and RNA, and a diet high in purine.

<span class="mw-page-title-main">Vernakalant</span> Medication for the acute treatment of atrial fibrillation

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A xanthine oxidase inhibitor is any substance that inhibits the activity of xanthine oxidase, an enzyme involved in purine metabolism. In humans, inhibition of xanthine oxidase reduces the production of uric acid, and several medications that inhibit xanthine oxidase are indicated for treatment of hyperuricemia and related medical conditions including gout. Xanthine oxidase inhibitors are being investigated for management of reperfusion injury.

<span class="mw-page-title-main">Ixazomib</span> Chemical compound

Ixazomib is a drug for the treatment of multiple myeloma, a type of white blood cell cancer, in combination with other drugs. It is taken by mouth in the form of capsules.

Lesinurad/allopurinol is a fixed-dose combination drug for the treatment of gout. It contains 200 mg of lesinurad and 300 mg of allopurinol. In August 2017, the US Food and Drug Administration approved it for the treatment of hyperuricemia associated with gout in patients for whom target serum uric acid levels have not been achieved with allopurinol alone. It was approved for medical use in the European Union in August 2018. In February 2019, it was discontinued by its manufacturer for business reasons and is no longer available.

Bempedoic acid, sold under the brand name Nexletol among others, is a medication for the treatment of hypercholesterolemia.

Bempedoic acid/ezetimibe, sold under the brand name Nexlizet among others, is a fixed-dose combination medication used for the treatment of high cholesterol. It is a combination of bempedoic acid and ezetimibe.

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. 1 2 3 "Zurampic (lesinurad) Tablets, for Oral Use. Full Prescribing Information" (PDF). AstraZeneca AB, S-151 85 Sodertalje, Sweden. Archived from the original (PDF) on 24 December 2015. Retrieved 23 December 2015.
  3. 1 2 "Drug Trial Snapshot: Zurampic". US Food and Drug Administration. 22 December 2015. Retrieved 14 October 2018.
  4. ↑ "EPAR summary for the public" (PDF). EMA. 13 March 2016.
  5. ↑ "Duzallo and Zurampic". Ironwood Pharmaceuticals. Archived from the original on 10 August 2020. Retrieved 31 July 2020.
  6. ↑ "Duzallo". European Medicines Agency. The European Union. 17 September 2018. Retrieved 2 October 2020.
  7. 1 2 3 4 5 6 7 8 9 "Zurampic: EPAR – Product Information" (PDF). European Medicines Agency. 6 July 2017.
  8. 1 2 3 4 5 6 7 8 FDA Professional Drug Information : Zurampic. Accessed 19 July 2017.
  9. 1 2 "Zurampic: EPAR – Public assessment report" (PDF). European Medicines Agency. 9 March 2016. pp. 18–19, 38–39.
  10. ↑ Wang J, Zeng W, Li S, Shen L, Gu Z, Zhang Y, et al. (March 2017). "Discovery and Assessment of Atropisomers of (±)-Lesinurad". ACS Medicinal Chemistry Letters. 8 (3): 299–303. doi:10.1021/acsmedchemlett.6b00465. PMC   5346995 . PMID   28337320.
  11. ↑ "Zurampic: EPAR – Public assessment report" (PDF). European Medicines Agency. 9 March 2016. p. 9.

Further reading

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