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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Lesinurad Therapy and CYP2C9 Genotype - Medical Genetics Summaries - NCBI Bookshelf</title>
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<meta name="citation_date" content="2019/02/11">
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<meta name="citation_author" content="Laura Dean">
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<meta name="citation_keywords" content="Lesinurad">
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<meta name="citation_keywords" content="lesinurad response">
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<meta name="citation_keywords" content="Zurampic">
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<meta name="citation_keywords" content="Duzallo">
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id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK537366_"><span class="title" itemprop="name">Lesinurad Therapy and <i>CYP2C9</i> Genotype</span></h1><p class="contribs">Dean L.</p><p class="fm-aai"><a href="#_NBK537366_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 10 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="lesinurad.Introduction" itemprop="description"><h2 id="_lesinurad_Introduction_">Introduction</h2><p>Lesinurad (brand name Zurampic) is a urate transport inhibitor used in the treatment of gout. Gout is one of the most common types of inflammatory arthritis, affecting approximately 3% of adults worldwide. It is caused by the accumulation of urate crystals in joints. The long-term management of gout includes reducing risk factors (e.g., obesity, alcohol use, diuretic use, poor renal function), and medication to lower uric acid levels.</p><p>Lesinurad reduces the high level of uric acid (hyperuricemia) associated with gout. Lesinurad should only be used in combination with a xanthine oxidase inhibitor (e.g., allopurinol, febuxostat) –– the risk of acute renal failure is increased if lesinurad is used alone.</p><p>The addition of lesinurad to gout treatment is reserved for patients who have failed to achieve their target uric acid level despite being treated with a xanthine oxidase inhibitor. Xanthine oxidase inhibitors reduce uric acid by inhibiting its production, whereas lesinurad reduces uric acid by blocking its reabsorption in the kidney.</p><p>Lesinurad is primarily metabolized by CYP2C9 to several inactive metabolites. Individuals who lack CYP2C9 activity (“CYP2C9 poor metabolizers”) have an increased exposure to lesinurad, and an increased risk of side effects. Adverse reactions of lesinurad therapy include kidney stones and other kidney problems. Lesinurad is also associated with an increased risk of cardiovascular events.</p><p>The FDA-approved drug label for lesinurad states that lesinurad should be used with caution in CYP2C9 poor metabolizers, but does not provide specific dose adjustments in this group (<a href="/books/NBK537366/table/lesinurad.T.the_fda_2018_drug_label_for/?report=objectonly" target="object" rid-ob="figoblesinuradTthefda2018druglabelfor">Table 1</a>). The standard dose of lesinurad is 200 mg daily (<a class="bibr" href="#lesinurad.REF.1" rid="lesinurad.REF.1">1</a>). Lesinurad is contraindicated in patients with severe impairment of kidney function (e.g., kidney transplant and hemodialysis patients) as well as individuals with tumor lysis syndrome or Lesch-Nyhan syndrome.</p></div><div class="h2"></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figlesinuradTthefda2018druglabelfor"><a href="/books/NBK537366/table/lesinurad.T.the_fda_2018_drug_label_for/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figoblesinuradTthefda2018druglabelfor"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="lesinurad.T.the_fda_2018_drug_label_for"><a href="/books/NBK537366/table/lesinurad.T.the_fda_2018_drug_label_for/?report=objectonly" target="object" rid-ob="figoblesinuradTthefda2018druglabelfor">Table 1. </a></h4><p class="float-caption no_bottom_margin">The FDA (2018) Drug Label for Lesinurad. CYP2C9 Inhibitors, CYP2C9 Poor Metabolizers, and CYP2C9 Inducers. </p></div></div><div id="lesinurad.Drug_Lesinurad"><h2 id="_lesinurad_Drug_Lesinurad_">Drug: Lesinurad</h2><p>Lesinurad is a urate transporter inhibitor used to treat the increased level of uric acid in patients with gout. Lesinurad should only be used for patients with gout who have high levels of uric acid despite being treated with a xanthine oxidase inhibitor, and lesinurad should only be used in combination with a xanthine oxidase inhibitor (<a class="bibr" href="#lesinurad.REF.1" rid="lesinurad.REF.1">1</a>).</p><p>Gout is one of the most common types of inflammatory arthritis. It affects approximately 3% of adults worldwide, and the prevalence is increasing (<a class="bibr" href="#lesinurad.REF.2" rid="lesinurad.REF.2">2</a>-<a class="bibr" href="#lesinurad.REF.5" rid="lesinurad.REF.5">5</a>). Gout is caused by the body’s inflammatory response to an accumulation of urate crystals. A high level of uric acid in the blood (above 6.8 mg/dl indicates hyperuricemia) always precedes gout. However, the majority of individuals with hyperuricemia do not develop urate crystal deposits and gout, and lesinurad should not be used to treat asymptomatic hyperuricemia.</p><p>Patients with gout usually have an extremely painful, swollen joint –– this is known as acute gouty arthritis. A single joint in the lower limb is most commonly affected (e.g., the base of the big toe, knee), and the joint will remain painful for at least several days. In a minority, persistent hyperuricemia leads to chronic gout, which is associated with deposits of urate crystals known as tophi.</p><p>Medications for gout focus on lowering uric acid levels. There are 3 main types of drugs:</p><ul><li class="half_rhythm"><div>xanthine oxidase inhibitors that decrease the production of uric acid (e.g., allopurinol, febuxostat)</div></li><li class="half_rhythm"><div>uricosuric drugs that inhibit the reabsorption of uric acid in the kidneys (e.g., benzbromarone, probenecid, and lesinurad)</div></li><li class="half_rhythm"><div>uricase drugs that convert uric acid to a more soluble metabolite (e.g., pegloticase, rasburicase)</div></li></ul><p>Lesinurad is the newest uricosuric drug to be approved for gout. However, since the introduction of allopurinol in the 1960s, uricosuric drugs have not been commonly used. This is because they are associated with numerous drug interactions and side effects (<a class="bibr" href="#lesinurad.REF.6" rid="lesinurad.REF.6">6</a>-<a class="bibr" href="#lesinurad.REF.8" rid="lesinurad.REF.8">8</a>).</p><p>Like other uricosuric drugs, lesinurad inhibits the urate transporter 1 (URAT1), which mediates reabsorption of uric acid in the kidney, and the organic anion transporter 4 (OAT4), which is implicated with hyperuricemia associated with diuretic use. But unlike probenecid, lesinurad does not appear to inhibit OAT1 or OAT3, and this may result in fewer drug interactions and adverse events (<a class="bibr" href="#lesinurad.REF.9" rid="lesinurad.REF.9">9</a>). However, like all uricosuric agents, lesinurad is associated with the development of kidney stones (<a class="bibr" href="#lesinurad.REF.10" rid="lesinurad.REF.10">10</a>-<a class="bibr" href="#lesinurad.REF.12" rid="lesinurad.REF.12">12</a>).</p><p>There are many risk factors that may contribute to triggering a gout attack. These include dietary factors, dehydration, and alcohol use. In addition, medications that alter serum concentrations of uric acid, such as diuretics and gout medications, can trigger gout. Therefore, when starting medical therapy for gout, it is recommended that urate levels are reduced slowly (e.g., 1–2 mg/dl per month). To prevent flare-ups, an additional drug such as colchicine may be used to reduce swelling and pain until target serum levels have been achieved and maintained (<a class="bibr" href="#lesinurad.REF.13" rid="lesinurad.REF.13">13</a>).</p><p>Allopurinol is the mainstay treatment for gout –– it is effective in lowering uric acid levels, reduces the frequency of gout attacks, and contributes to resolving tophi. However, in individuals who are carriers of the genetic variant <i>HLA-B*58:01</i>, allopurinol is associated with severe cutaneous adverse reactions (SCAR) (<a class="bibr" href="#lesinurad.REF.14" rid="lesinurad.REF.14">14</a>, <a class="bibr" href="#lesinurad.REF.15" rid="lesinurad.REF.15">15</a>). For these individuals, febuxostat may be the safer choice –– it is a structurally different xanthine oxidase inhibitor that is not associated with SCAR (<a class="bibr" href="#lesinurad.REF.13" rid="lesinurad.REF.13">13</a>).</p><p>In general, when allopurinol is used at an adequate dose, levels of uric acid can reach the target range of below 6 mg/dl (<a class="bibr" href="#lesinurad.REF.16" rid="lesinurad.REF.16">16</a>, <a class="bibr" href="#lesinurad.REF.17" rid="lesinurad.REF.17">17</a>). If uric acid levels stay in this range, subsequent attacks of gout are unlikely. However, allopurinol therapy is needed long term; compliance is often poor; therefore, patient education is important (<a class="bibr" href="#lesinurad.REF.11" rid="lesinurad.REF.11">11</a>, <a class="bibr" href="#lesinurad.REF.18" rid="lesinurad.REF.18">18</a>).</p><p>Several trials have shown that the addition of lesinurad to allopurinol therapy leads to a greater reduction in uric acid levels, and at the recommended dose of 200 mg daily, lesinurad is generally well tolerated (<a class="bibr" href="#lesinurad.REF.19" rid="lesinurad.REF.19">19</a>-<a class="bibr" href="#lesinurad.REF.21" rid="lesinurad.REF.21">21</a>).</p><p>Adverse effects associated with lesinurad therapy include rising creatinine levels, which are often reversible, nephrolithiasis (kidney stones), urolithiasis (stones in the bladder or urinary tract), and acute renal failure – which is associated more with lesinurad monotherapy (not recommended by the FDA) at the higher drug dose of 400 mg (twice the FDA-approved dose). Lesinurad is also associated with an increased risk of cardiovascular events (<a class="bibr" href="#lesinurad.REF.22" rid="lesinurad.REF.22">22</a>).</p><p>Patients with moderate renal impairment experience a 150% increase in exposure to lesinurad, which should be used with caution in these patients (<a class="bibr" href="#lesinurad.REF.23" rid="lesinurad.REF.23">23</a>). Lesinurad is contraindicated in individuals with severe renal impairment, end stage renal disease, kidney transplant recipients, or patients on dialysis as well as individuals with tumor lysis syndrome or Lesch-Nyhan syndrome.</p><p>Lesinurad is primarily metabolized by CYP2C9 to several inactive metabolites. The co-administration of lesinurad with moderate inducers of CYP2C9 (e.g., rifampin, carbamazepine), may decrease the therapeutic effect of lesinurad by reducing its exposure.</p><p>In contrast, the co-administration of lesinurad with drugs that are CYP2C9 inhibitors (e.g., fluconazole, amiodarone), or the administration of lesinurad to patients who lack CYP2C9 activity (“CYP2C9 poor metabolizers”), will increase exposure to lesinurad. This may increase the risk of adverse reactions.</p><p>Therefore, lesinurad should be used with caution in patients with moderate kidney disease, patients taking CYP2C9 inhibitors, and patients who are CYP2C9 poor metabolizers (<a class="bibr" href="#lesinurad.REF.1" rid="lesinurad.REF.1">1</a>, <a class="bibr" href="#lesinurad.REF.24" rid="lesinurad.REF.24">24</a>).</p></div><div id="lesinurad.Gene_CYP2C9"><h2 id="_lesinurad_Gene_CYP2C9_">Gene: CYP2C9</h2><p>The cytochrome P450 superfamily (CYP450) is a large and diverse group of enzymes that form the major system for metabolizing lipids, hormones, toxins, and drugs in the liver. The CYP450 genes are very polymorphic and can result in reduced, absent, or increased enzyme activity (<a class="bibr" href="#lesinurad.REF.25" rid="lesinurad.REF.25">25</a>).</p><p>The <i>CYP2C9</i> gene is highly polymorphic, with approximately 60 known alleles. <i>CYP2C9*1</i> is considered the wild-type allele when no variants are detected and is categorized as normal enzyme activity (<a class="bibr" href="#lesinurad.REF.26" rid="lesinurad.REF.26">26</a>). Individuals who have 2 normal-function alleles (e.g., <i>CYP2C9 *1/*1</i>) are classified as “normal metabolizers” (<a href="/books/NBK537366/table/lesinurad.T.assignment_of_likely_cyp2c9/?report=objectonly" target="object" rid-ob="figoblesinuradTassignmentoflikelycyp2c9">Table 2</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figlesinuradTassignmentoflikelycyp2c9"><a href="/books/NBK537366/table/lesinurad.T.assignment_of_likely_cyp2c9/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figoblesinuradTassignmentoflikelycyp2c9"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="lesinurad.T.assignment_of_likely_cyp2c9"><a href="/books/NBK537366/table/lesinurad.T.assignment_of_likely_cyp2c9/?report=objectonly" target="object" rid-ob="figoblesinuradTassignmentoflikelycyp2c9">Table 2. </a></h4><p class="float-caption no_bottom_margin">Assignment of likely <i>CYP2C9</i> Phenotype based on Genotype (CPIC, 2014) </p></div></div><p>Two allelic variants associated with reduced enzyme activity are <i>CYP2C9*2</i> and <i>*3</i>. The <i>*2</i> allele is more common in Caucasian (10-20%) than Asian (1-3%) or African (0-6%) populations. The <i>*3</i> allele is less common (<10% in most populations) and is extremely rare in African populations. In African-Americans, the <i>CYP2C9*5</i>, <i>*6</i>, <i>*8</i> and <i>*11</i> alleles are more common (<a class="bibr" href="#lesinurad.REF.28" rid="lesinurad.REF.28">28</a>-<a class="bibr" href="#lesinurad.REF.30" rid="lesinurad.REF.30">30</a>).</p></div><div id="lesinurad.Linking_Gene_Variation_with_Tr"><h2 id="_lesinurad_Linking_Gene_Variation_with_Tr_">Linking Gene Variation with Treatment Response</h2><p>Currently, data are limited on the relationship between an individual’s <i>CYP2C9</i> status and their response to lesinurad therapy.</p><p>The lesinurad drug label discusses an analysis of a small group of patients –– 2 patients were CYP2C9 poor metabolizers, and 41 were normal CYP2C9 metabolizers. At the 400 mg dose of lesinurad (which is twice the recommended dose of 200 mg daily), exposure to lesinurad was approximately 1.8 times higher in poor metabolizers compared to normal metabolizers. Therefore, the label states that lesinurad should be used with caution in CYP2C9 poor metabolizers.</p><p>The drug label also states that lesinurad should be used with caution in patients taking drugs that are CYP2C9 inhibitors (because of increased exposure and risk of side effects) and in patients taking drugs that are CYP2C9 inducers (because of decreased exposure and risk of reduced therapeutic effect). Drugs that inhibit CYP2C9 include fluconazole (antifungal agent) and amiodarone (antiarrhythmic); and drugs that induce CYP2C9 include rifampin (antibiotic) and carbamazepine (anti-seizure drug) (<a class="bibr" href="#lesinurad.REF.1" rid="lesinurad.REF.1">1</a>).</p></div><div id="lesinurad.Genetic_Testing"><h2 id="_lesinurad_Genetic_Testing_">Genetic Testing</h2><p>Clinical genotyping tests are available for several <i>CYP2C9</i> alleles. The NIH Genetic Testing Registry (GTR) displays genetic tests that are currently available for <a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=%20CN248784" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">lesinurad response</a> and for the <a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=1559%5Bgeneid%5D" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri"><i>CYP2C9</i> gene</a>.</p><p>The <i>CYP2C9</i> variants that are routinely tested for include <i>CYP2C9*2</i> and <i>*3</i>. Usually the results are reported as a diplotype, such as <i>CYP2C9 *1/*1</i>, and may also include an interpretation of the patient’s predicted metabolizer phenotype (normal, intermediate, or poor). <a href="/books/NBK537366/table/lesinurad.T.assignment_of_likely_cyp2c9/?report=objectonly" target="object" rid-ob="figoblesinuradTassignmentoflikelycyp2c9">Table 2</a> summarizes common CYP2C9 phenotypes.</p></div><div id="lesinurad.Therapeutic_Recommendations_ba"><h2 id="_lesinurad_Therapeutic_Recommendations_ba_">Therapeutic Recommendations based on Genotype</h2><p><b>This section contains excerpted</b><sup><a href="#lesinurad.FN1">1</a></sup>
|
|
<b>information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.</b></p><div id="lesinurad.2018_Statement_from_the_US_Foo"><h3>2018 Statement from the US Food and Drug Administration (FDA)</h3><p>Lesinurad exposure is increased when lesinurad is co-administered with inhibitors of CYP2C9, and in CYP2C9 poor metabolizers. Lesinurad should be used with caution in patients taking moderate inhibitors of CYP2C9 (e.g., fluconazole, amiodarone), and in CYP2C9 poor metabolizers.</p><p>Lesinurad exposure is decreased when lesinurad is co-administered with moderate inducers of CYP2C9 (e.g., rifampin, carbamazepine), which may decrease the therapeutic effect of lesinurad.</p><p>[…]</p><p>Patients who are CYP2C9 poor metabolizers are deficient in CYP2C9 enzyme activity. A cross-study pharmacogenomic analysis assessed the association between CYP2C9 polymorphism and lesinurad exposure in patients receiving single or multiple doses of lesinurad at 200 mg, 400 mg or 600 mg. At the 400 mg dose, lesinurad exposure was approximately 1.8-fold higher in CYP2C9 poor metabolizers (i.e., subjects with <i>CYP2C9 *2/*2</i> [N=1], and <i>*3/*3</i> [N=1] genotype) compared to CYP2C9 extensive metabolizers (i.e., <i>CYP2C9 *1/*1</i> [N=41] genotype). Use with caution in CYP2C9 poor metabolizers, and in patients taking moderate inhibitors of CYP2C9.</p><p><b>Please review the complete therapeutic recommendations that are located here:</b> (<a class="bibr" href="#lesinurad.REF.1" rid="lesinurad.REF.1">1</a>).</p></div></div><div id="lesinurad.Nomenclature_for_selected_CYP2"><h2 id="_lesinurad_Nomenclature_for_selected_CYP2_">Nomenclature for selected <i>CYP2C9</i> alleles</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figlesinuradTe"><a href="/books/NBK537366/table/lesinurad.Te/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figoblesinuradTe"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="lesinurad.Te"><a href="/books/NBK537366/table/lesinurad.Te/?report=objectonly" target="object" rid-ob="figoblesinuradTe">Table</a></h4></div></div></div><div id="lesinurad.Acknowledgments"><h2 id="_lesinurad_Acknowledgments_">Acknowledgments</h2><p>The author would like to thank Andy R. Eugene, MD, PhD, Assistant Professor of Pharmacogenomics, Bernard J. Dunn School of Pharmacy, Shenandoah University - Fairfax Inova Center for Personalized Health, Fairfax, VA, USA; Houda Hachad, PharmD, MRes, Chief Science Officer, Translational Software, Seattle, WA, USA; Neil William McGill, Clinical Associate Professor, University of Sydney, and Rheumatologist, Royal Prince Alfred Hospital, Syndey, NSW, Australia; Mohamed Nagy, Clinical Pharmacist, Head of the Personalised Medication Management Unit, Department of Pharmaceutical Services, Children's Cancer Hospital, Cairo, Egypt; and Chakradhara Rao S. Uppugunduri, Maître-Assistant at the CANSEARCH Laboratory, University of Geneva, Geneva, Switzerland, for reviewing this summary.</p></div><div id="lesinurad.References"><h2 id="_lesinurad_References_">References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="lesinurad.REF.1">ZURAMPIC- lesinurad tablet, film coated [Packet insert]. Ironwood Pharmaceuticals.; January 2018. Available from: <a href="https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef9e7711-f478-4e35-bf4e-6021c8457e3b" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://dailymed<wbr style="display:inline-block"></wbr>​.nlm<wbr style="display:inline-block"></wbr>​.nih.gov/dailymed/drugInfo<wbr style="display:inline-block"></wbr>​.cfm?setid=ef9e7711-f478-4e35-bf4e-6021c8457e3b</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="lesinurad.REF.2">Juraschek S.P., Miller E.R. 3rd, Gelber A.C. Body mass index, obesity, and prevalent gout in the United States in 1988-1994 and 2007-2010. <span><span class="ref-journal">Arthritis Care Res (Hoboken). </span>2013 Jan;<span class="ref-vol">65</span>(1):127–32.</span> [<a href="/pmc/articles/PMC3482278/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3482278</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22778033" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22778033</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="lesinurad.REF.3">Roddy E., Choi H.K. Epidemiology of gout. <span><span class="ref-journal">Rheum Dis Clin North Am. </span>2014 May;<span class="ref-vol">40</span>(2):155–75.</span> [<a href="/pmc/articles/PMC4119792/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4119792</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24703341" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24703341</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="lesinurad.REF.4">Smith E., Hoy D., Cross M., Merriman T.R., et al. The global burden of gout: estimates from the Global Burden of Disease 2010 study. <span><span class="ref-journal">Ann Rheum Dis. </span>2014 Aug;<span class="ref-vol">73</span>(8):1470–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24590182" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24590182</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="lesinurad.REF.5">McGill N.W. The epidemiology and treatment of gout. <span><span class="ref-journal">Open Access Rheumatol. </span>2011;<span class="ref-vol">3</span>:73–82.</span> [<a href="/pmc/articles/PMC5074782/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5074782</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27790006" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27790006</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="lesinurad.REF.6">Schlee S., Bollheimer L.C., Bertsch T., Sieber C.C., et al. Crystal arthritides - gout and calcium pyrophosphate arthritis : Part 3: Treatment. <span><span class="ref-journal">Z Gerontol Geriatr. </span>2018 Feb 28;<span class="ref-vol">51</span>(6):703–710.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28246893" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28246893</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="lesinurad.REF.7">Gupta A., Sharma P.K., Misra A.K., Singh S. Lesinurad: A significant advancement or just another addition to existing therapies of gout? <span><span class="ref-journal">J Pharmacol Pharmacother. </span>2016 Oct-Dec;<span class="ref-vol">7</span>(4):155–158.</span> [<a href="/pmc/articles/PMC5242027/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5242027</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28163535" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28163535</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="lesinurad.REF.8">Miner J.N., Tan P.K., Hyndman D., Liu S., et al. Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney. <span><span class="ref-journal">Arthritis Res Ther. </span>2016 Oct 03;<span class="ref-vol">18</span>(1):214.</span> [<a href="/pmc/articles/PMC5048659/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5048659</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27716403" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27716403</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="lesinurad.REF.9">Soskind R., Abazia D.T., Bridgeman M.B. Updates on the treatment of gout, including a review of updated treatment guidelines and use of small molecule therapies for difficult-to-treat gout and gout flares. <span><span class="ref-journal">Expert Opin Pharmacother. </span>2017 Aug;<span class="ref-vol">18</span>(11):1115–1125.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28658988" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28658988</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="lesinurad.REF.10">Davies K., Bukhari M.A.S. Recent pharmacological advances in the management of gout. <span><span class="ref-journal">Rheumatology (Oxford). </span>2018 Sep 14;<span class="ref-vol">57</span>(6):951–958.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28968896" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28968896</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="lesinurad.REF.11">Hill-McManus D., Soto E., Marshall S., Lane S., et al. Impact of non-adherence on the safety and efficacy of uric acid-lowering therapies in the treatment of gout. <span><span class="ref-journal">Br J Clin Pharmacol. </span>2018 Sep 09;<span class="ref-vol">84</span>(1):142–152.</span> [<a href="/pmc/articles/PMC5736842/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5736842</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28888218" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28888218</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="lesinurad.REF.12">Lesinurad (Zurampic) for gout-associated hyperuricemia. <span><span class="ref-journal">Med Lett Drugs Ther. </span>2016 Nov 21;<span class="ref-vol">58</span>(1508):148–150.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27849193" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27849193</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="lesinurad.REF.13">UpToDate. Prevention of recurrent gout: Pharmacologic urate-lowering therapy and treatment of tophi [Cited October 12, 2017]. Available from: <a href="https://www.uptodate.com/contents/prevention-of-recurrent-gout-pharmacologic-urate-lowering-therapy-and-treatment-of-tophi" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.uptodate<wbr style="display:inline-block"></wbr>​.com/contents/prevention-of-recurrent-gout-pharmacologic-urate-lowering-therapy-and-treatment-of-tophi</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="lesinurad.REF.14">Hershfield M.S., Callaghan J.T., Tassaneeyakul W., Mushiroda T., et al. Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. <span><span class="ref-journal">Clin Pharmacol Ther. </span>2013 Feb;<span class="ref-vol">93</span>(2):153–8.</span> [<a href="/pmc/articles/PMC3564416/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3564416</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23232549" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23232549</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="lesinurad.REF.15">Dean, L., Allopurinol Therapy and HLA-B*58:01 Genotype, in Medical Genetics Summaries, V. Pratt, et al., Editors. 2012: Bethesda (MD). [<a href="https://pubmed.ncbi.nlm.nih.gov/28520356" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28520356</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="lesinurad.REF.16">Singh J.A. Lesinurad combination therapy with allopurinol in gout: do CLEAR studies make the treatment of gout clearer? <span><span class="ref-journal">Ann Rheum Dis. </span>2017 May;<span class="ref-vol">76</span>(5):779–781.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28039184" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28039184</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="lesinurad.REF.17">Abeles A.M. Lesinurad in Combination With Allopurinol: Risk Without Reward? Comment on the Article by Saag et al. <span><span class="ref-journal">Arthritis Rheumatol. </span>2017 May;<span class="ref-vol">69</span>(5):1122.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27992699" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27992699</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="lesinurad.REF.18">Engel B., Just J., Bleckwenn M., Weckbecker K. Treatment Options for Gout. <span><span class="ref-journal">Dtsch Arztebl Int. </span>2017 Mar 31;<span class="ref-vol">114</span>(13):215–222.</span> [<a href="/pmc/articles/PMC5624445/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5624445</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28434436" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28434436</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="lesinurad.REF.19">Bardin T., Keenan R.T., Khanna P.P., Kopicko J., et al. Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study). <span><span class="ref-journal">Ann Rheum Dis. </span>2017 May;<span class="ref-vol">76</span>(5):811–820.</span> [<a href="/pmc/articles/PMC5530336/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5530336</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27821644" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27821644</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>20.</dt><dd><div class="bk_ref" id="lesinurad.REF.20">Deeks E.D. Lesinurad: A Review in Hyperuricaemia of Gout. <span><span class="ref-journal">Drugs Aging. </span>2017 May;<span class="ref-vol">34</span>(5):401–410.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28425024" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28425024</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>21.</dt><dd><div class="bk_ref" id="lesinurad.REF.21">Terkeltaub R. Emerging uricosurics for gout. <span><span class="ref-journal">Expert Rev Clin Pharmacol. </span>2017 Mar;<span class="ref-vol">10</span>(3):247–249.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27937050" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27937050</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>22.</dt><dd><div class="bk_ref" id="lesinurad.REF.22">Pascart T., Richette P. Current and future therapies for gout. <span><span class="ref-journal">Expert Opin Pharmacother. </span>2017 Aug;<span class="ref-vol">18</span>(12):1201–1211.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28689430" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28689430</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>23.</dt><dd><div class="bk_ref" id="lesinurad.REF.23">FDA. Center of Drug Evaluation and Research. Clinical Pharmacology Review. Lesinurad.; Decmber 2014. Available from: <a href="https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207988Orig1s000ClinPharmR.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.accessdata<wbr style="display:inline-block"></wbr>​.fda.gov/drugsatfda_docs<wbr style="display:inline-block"></wbr>​/nda/2015/207988Orig1s000ClinPharmR.pdf</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>24.</dt><dd><div class="bk_ref" id="lesinurad.REF.24">Shah V., Yang C., Shen Z., Kerr B.M., et al. Metabolism and disposition of lesinurad, a uric acid reabsorption inhibitor, in humans. <span><span class="ref-journal">Xenobiotica. </span>2018 Sep 12;:1–12.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30117757" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30117757</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>25.</dt><dd><div class="bk_ref" id="lesinurad.REF.25">Kirchheiner J., Brockmoller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. <span><span class="ref-journal">Clin Pharmacol Ther. </span>2005 Jan;<span class="ref-vol">77</span>(1):1–16.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15637526" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15637526</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>26.</dt><dd><div class="bk_ref" id="lesinurad.REF.26">Caudle K.E., Rettie A.E., Whirl-Carrillo M., Smith L.H., et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. <span><span class="ref-journal">Clin Pharmacol Ther. </span>2014 Nov;<span class="ref-vol">96</span>(5):542–8.</span> [<a href="/pmc/articles/PMC4206662/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4206662</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25099164" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25099164</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>27.</dt><dd><div class="bk_ref" id="lesinurad.REF.27">Hicks J.K., Sangkuhl K., Swen J.J., Ellingrod V.L., et al. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. <span><span class="ref-journal">Clin Pharmacol Ther. </span>2017 Dec 20;<span class="ref-vol">102</span>(1):37–44.</span> [<a href="/pmc/articles/PMC5478479/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5478479</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27997040" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27997040</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>28.</dt><dd><div class="bk_ref" id="lesinurad.REF.28">Sistonen J., Fuselli S., Palo J.U., Chauhan N., et al. Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales. <span><span class="ref-journal">Pharmacogenetics and genomics. </span>2009 Feb;<span class="ref-vol">19</span>(2):170–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19151603" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19151603</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>29.</dt><dd><div class="bk_ref" id="lesinurad.REF.29">Solus J.F., Arietta B.J., Harris J.R., Sexton D.P., et al. Genetic variation in eleven phase I drug metabolism genes in an ethnically diverse population. <span><span class="ref-journal">Pharmacogenomics. </span>2004 Oct;<span class="ref-vol">5</span>(7):895–931.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15469410" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15469410</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>30.</dt><dd><div class="bk_ref" id="lesinurad.REF.30">Lee C.R., Goldstein J.A., Pieper J.A. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. <span><span class="ref-journal">Pharmacogenetics. </span>2002 Apr;<span class="ref-vol">12</span>(3):251–63.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11927841" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11927841</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>31.</dt><dd><div class="bk_ref" id="lesinurad.REF.31">Kalman L.V., Agundez J., Appell M.L., Black J.L., et al. Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting. <span><span class="ref-journal">Clin Pharmacol Ther. </span>2016 Feb;<span class="ref-vol">99</span>(2):172–85.</span> [<a href="/pmc/articles/PMC4724253/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4724253</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26479518" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26479518</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>32.</dt><dd><div class="bk_ref" id="lesinurad.REF.32">den Dunnen, J.T., R.
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Dalgleish, D.R.
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Maglott, R.K.
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Hart, et al. <span class="ref-title">HGVS Recommendations for the Description of Sequence Variants: 2016 Update. </span><span class="ref-journal">Hum Mutat</span>, 2016.37(6): p.564-9.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/26931183" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26931183</span></a>]</div></dd></dl></dl></div><h2 id="NBK537366_footnotes">Footnotes</h2><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>
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<sup>1</sup>
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</dt><dd><div id="lesinurad.FN1"><p class="no_top_margin"> The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labelled all formulations containing the generic drug.</p></div></dd></dl></dl><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK537366_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Laura Dean</span>, MD<sup>1</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> NCBI<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin.mln.ibcn@sgm" class="oemail">vog.hin.mln.ibcn@sgm</a></div></div><h3>Publication History</h3><p class="small">Created: <span itemprop="datePublished">February 11, 2019</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a><p class="small">All Medical Genetics Summaries content, except where otherwise noted, is licensed under a Creative Commons <a href="https://creativecommons.org/licenses/by/4.0/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">Attribution 4.0 International (CC BY 4.0)</a> license which permits copying, distribution, and adaptation of the work, provided the original work is properly cited and any changes from the original work are properly indicated. Any altered, transformed, or adapted form of the work may only be distributed under the same or similar license to this one.</p></div></div><h3>Publisher</h3><p><a href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=books" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Center for Biotechnology Information (US)</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>Dean L. Lesinurad Therapy and CYP2C9 Genotype. 2019 Feb 11. In: Pratt VM, Scott SA, Pirmohamed M, et al., editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gtrbook/lecanemab/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gtrbook/maraviroc/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figoblesinuradTthefda2018druglabelfor"><div id="lesinurad.T.the_fda_2018_drug_label_for" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>The FDA (2018) Drug Label for Lesinurad. CYP2C9 Inhibitors, CYP2C9 Poor Metabolizers, and CYP2C9 Inducers.</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK537366/table/lesinurad.T.the_fda_2018_drug_label_for/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lesinurad.T.the_fda_2018_drug_label_for_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_lesinurad.T.the_fda_2018_drug_label_for_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Phenotype</th><th id="hd_h_lesinurad.T.the_fda_2018_drug_label_for_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Recommendations</th></tr></thead><tbody><tr><td headers="hd_h_lesinurad.T.the_fda_2018_drug_label_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CYP2C9 Poor metabolizer</td><td headers="hd_h_lesinurad.T.the_fda_2018_drug_label_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lesinurad exposure is increased when lesinurad is co-administered with inhibitors of CYP2C9 and in CYP2C9 poor metabolizers. Lesinurad should be used with caution in patients taking moderate inhibitors of CYP2C9 (e.g., fluconazole, amiodarone), and in CYP2C9 poor metabolizers.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">This table is adapted from (<a class="bibr" href="#lesinurad.REF.1" rid="lesinurad.REF.1">1</a>).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figoblesinuradTassignmentoflikelycyp2c9"><div id="lesinurad.T.assignment_of_likely_cyp2c9" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Assignment of likely <i>CYP2C9</i> Phenotype based on Genotype (CPIC, 2014)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK537366/table/lesinurad.T.assignment_of_likely_cyp2c9/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lesinurad.T.assignment_of_likely_cyp2c9_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Likely phenotype<sup>a</sup></th><th id="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Genotype</th><th id="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Examples of diplotypes</th></tr></thead><tbody><tr><td headers="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Ultrarapid metabolizer<br />(increased activity)<br />(frequency unknown)</td><td headers="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Unknown – currently there are no known increased activity alleles</td><td headers="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Unknown</td></tr><tr><td headers="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Normal metabolizer<br />(normal activity) <br />(approximately 91% of individuals)</td><td headers="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">An individual with 2 normal-function alleles</td><td headers="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">*1/*1</td></tr><tr><td headers="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Intermediate metabolizer <br />(heterozygote or intermediate activity) <br />(approximately 8% of individuals)<sup>b</sup></td><td headers="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">An individual with one normal-function allele plus one decreased-function allele</td><td headers="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">*1/*3, *1/*2</td></tr><tr><td headers="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Poor metabolizer <br />(homozygous variant, low or deficient activity) <br />(approximately 1% of individuals)</td><td headers="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">An individual with 2 decreased-function alleles</td><td headers="hd_h_lesinurad.T.assignment_of_likely_cyp2c9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">*2/*2, *3/*3, *2/*3</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Note: There are no known cases of CYP2C9 ultrarapid metabolizers.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">a Global frequencies are approximate. Because haplotype frequencies vary considerably among popualations, please see (<a class="bibr" href="#lesinurad.REF.26" rid="lesinurad.REF.26">26</a>) for individual population frequencies.</p></div></dd></dl><dl class="bkr_refwrap"><dt><sup>b</sup>
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</dt><dd><div id="lesinurad.TF.2.1"><p class="no_margin">The enzyme activity in this grouping varies widely. Please see (<a class="bibr" href="#lesinurad.REF.26" rid="lesinurad.REF.26">26</a>) for activity ranges.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">This table is adapted from (<a class="bibr" href="#lesinurad.REF.26" rid="lesinurad.REF.26">26</a>). Note: The nomenclature used in this table reflects the standardized pharmacogenetic terms proposed by the Clinical Pharmacogenetics Implementation Consortium (CPIC) (<a class="bibr" href="#lesinurad.REF.27" rid="lesinurad.REF.27">27</a>).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figoblesinuradTe"><div id="lesinurad.Te" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK537366/table/lesinurad.Te/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lesinurad.Te_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_lesinurad.Te_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_lesinurad.Te_1_1_1_1" style="text-align:left;vertical-align:top;">Common allele name</th><th id="hd_h_lesinurad.Te_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_lesinurad.Te_1_1_1_2" style="text-align:left;vertical-align:top;">Alternative names</th><th id="hd_h_lesinurad.Te_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:top;">HGVS reference sequence</th><th id="hd_h_lesinurad.Te_1_1_1_4" rowspan="2" scope="col" colspan="1" headers="hd_h_lesinurad.Te_1_1_1_4" style="text-align:left;vertical-align:top;">dbSNP reference identifier for allele location</th></tr><tr><th headers="hd_h_lesinurad.Te_1_1_1_3" id="hd_h_lesinurad.Te_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:top;">Coding</th><th headers="hd_h_lesinurad.Te_1_1_1_3" id="hd_h_lesinurad.Te_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Protein</th></tr></thead><tbody><tr><td headers="hd_h_lesinurad.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>CYP2C9*2</i>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">430C>T<br />Arg144Cys</td><td headers="hd_h_lesinurad.Te_1_1_1_3 hd_h_lesinurad.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/clinvar/variation/8409/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000771.3:c.430C>T</a>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_3 hd_h_lesinurad.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/clinvar/variation/8409/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000762.2:p.Arg144Cys</a>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs1799853" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs1799853</a>
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</td></tr><tr><td headers="hd_h_lesinurad.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>CYP2C9*3</i>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1075A>C<br />Ile359Leu</td><td headers="hd_h_lesinurad.Te_1_1_1_3 hd_h_lesinurad.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/clinvar/variation/8408/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000771.3:c.1075A>C</a>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_3 hd_h_lesinurad.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/clinvar/variation/8408/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000762.2:p.Ile359Leu</a>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs1057910" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs1057910</a>
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</td></tr><tr><td headers="hd_h_lesinurad.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>CYP2C9*5</i>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1080C>G<br />Asp360Glu</td><td headers="hd_h_lesinurad.Te_1_1_1_3 hd_h_lesinurad.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/variation/225984/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000771.3:c.1080C>G</a>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_3 hd_h_lesinurad.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/variation/225984/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000762.2:p.Asp360Glu</a>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs28371686" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs28371686</a>
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</td></tr><tr><td headers="hd_h_lesinurad.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>CYP2C9*6</i>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">818delA<br />Lys273Argfs</td><td headers="hd_h_lesinurad.Te_1_1_1_3 hd_h_lesinurad.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/variation/285601/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000771.3:c.817delA</a>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_3 hd_h_lesinurad.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/variation/285601/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000762.2:p.Lys273Argfs</a>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs9332131" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs9332131</a>
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</td></tr><tr><td headers="hd_h_lesinurad.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>CYP2C9*8</i>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">449G>A<br />Arg150His</td><td headers="hd_h_lesinurad.Te_1_1_1_3 hd_h_lesinurad.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/variation/226024/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000771.3:c.449G>A</a>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_3 hd_h_lesinurad.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/variation/226024/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000762.2:p.Arg150His</a>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs7900194" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs7900194</a>
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</td></tr><tr><td headers="hd_h_lesinurad.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>CYP2C9*11</i>
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</td><td headers="hd_h_lesinurad.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1003C>T<br />Arg335Trp</td><td headers="hd_h_lesinurad.Te_1_1_1_3 hd_h_lesinurad.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="/nuccore/189242609" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">NM_000771.3</a>:c.1003C>T</td><td headers="hd_h_lesinurad.Te_1_1_1_3 hd_h_lesinurad.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="/protein/13699818/?report=GenPept" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=genpept">NP_000762.2</a>:p.Arg335Trp</td><td headers="hd_h_lesinurad.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs28371685" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs28371685</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Note: the normal “wild-type” allele is <i>CYP2C9*1</i> and is reported when no variant is detected.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Pharmacogenetic Allele Nomenclature: International Workgroup Recommendations for Test Result Reporting (<a class="bibr" href="#lesinurad.REF.31" rid="lesinurad.REF.31">31</a>).</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Guidelines for the description and nomenclature of gene variations are available from the Human Genome Variation Society (HGVS (<a class="bibr" href="#lesinurad.REF.32" rid="lesinurad.REF.32">32</a>)).</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Nomenclature for cytochrome P450 enzymes is available from Pharmacogene Variation (<a href="http://www.pharmvar.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PharmVar</a>) Consortium.</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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