Lesinurad

Pharmacogenomics:

Lesinurad is metabolised primarily by CYP2C9 enzyme. Genetic polymorphism of CYP2C9 may affect the pharmacokinetics and clinical safety of lesinurad. CYP2C9*2 and *3 are identified as the allele variants which are associated with the reduction of CYP2C9 activity. The prevalence of *2 allele is more common in Caucasian (10-20%) than in the Asian (1-3%) or African (0-6%) populations, while the *3 allele is less common in most populations (<10%) and is extremely rare in African populations.

Individuals who are deficient in CYP2C9 enzyme activity are CYP2C9 poor metabolisers (carriers of 2 decreased function alleles e.g. *2/2, *3/*3, *2/*3).

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. CYP2C9 poor metabolisers (n=1) had a 1.8-fold higher lesinurad exposure as compared to CYP2C9 extensive metabolisers (n=41) after receiving the 400 mg dose.
CYP2C9 poor metabolisers should be treated with caution as the potential risk of renal-related adverse effects may be increased.

CrCl (mL/min)	Dosage
<30	Contraindicated.

Should be taken with food.

Patients with tumour lysis syndrome or Lesch-Nyhan syndrome, end-stage renal disease; on dialysis, or kidney transplant recipients. Severe renal (CrCl <30 mL/min) impairment.

CYP2C9 poor metabolisers. Pregnancy and lactation. Not recommended for patients taking allopurinol <300 mg daily (or <200 mg with CrCl <60 mL/min).

Significant: Gout flares, increased serum creatinine, renal failure, nephrolithiasis.
Gastrointestinal disorders: Gastroesophageal reflux disease.
Immune system disorders: Rarely, hypersensitivity reactions (e.g. photosensitivity).
Infections and infestations: Influenza.
Nervous system disorders: Headache.

Monitor renal function prior to treatment initiation and periodically thereafter.

Increased serum concentrations with moderate CYP2C9 inhibitors (e.g. fluconazole, amiodarone) and epoxide hydrolase inhibitors (e.g. valproic acid). Decreased serum concentrations with moderate CYP2C9 inducers (e.g. rifampicin, carbamazepine). Reduced plasma concentrations of CYP3A4 substrates (e.g. lovastatin, simvastatin, sildenafil, felodipine, nisoldipine, amlodipine). Decreased therapeutic effect of lesinurad with high-dose aspirin (>325 mg/day). Decreased serum concentration and effect of hormonal contraceptives (e.g. oestrogen).

Description:
Mechanism of Action: Lesinurad inhibits uric acid transporter 1 (URAT1) and organic anion transporter 4 (OAT4), increasing urinary excretion of uric acid, lowering plasma urate concentrations, and eventually reducing urate deposits in the tissues.
Pharmacokinetics:
Absorption: Rapidly absorbed from the gastrointestinal tract. Bioavailability: Approx 100%. Time to peak plasma concentrations: Within 1-4 hours.
Distribution: Volume of distribution: Approx 20 L. Plasma protein binding: >98%, mainly to albumin.
Metabolism: Undergoes oxidative metabolism mainly by CYP2C9.
Excretion: Via urine (63%; approx 30% as unchanged drug); faeces (32%). Elimination half-life: Approx 5 hours.

Source: National Center for Biotechnology Information. PubChem Database. Lesinurad, CID=53465279, https://pubchem.ncbi.nlm.nih.gov/compound/Lesinurad (accessed on Jan. 22, 2020)

Store between 20-25°C. Protect from light.

Thuốc trị tăng acid uric máu & bệnh gout

M04AB05 - lesinurad ; Belongs to the class of preparations increasing uric acid excretion. Used in the treatment of gout.

Dean L. Lesinurad Therapy and CYP2C9 Genotype. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US). 2019 Feb. PMID: 30742400

Annotation of EMA Label for Lesinurad and CYP2C9. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 16/10/2019.

Annotation of FDA Label for Lesinurad and CYP2C9. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 16/10/2019.

Anon. Lesinurad. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 16/10/2019.

Buckingham R (ed). Lesinurad. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 16/10/2019.

Zurampic (AstraZeneca Pharmaceuticals LP). U.S. FDA. https://www.fda.gov. Accessed 16/10/2019.

Zurampic (Grunenthal GmbH). European Medicines Agency [online]. Accessed 16/10/2019.

Zurampic (Ironwood Pharmaceuticals, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 16/10/2019.