1. Recent Advancement In Therapeutics ZURAMPIC ( LESINURAD)
Dr. Sachin Panwar JR-1 Department of Pharmacology KGMU , Lucknow

2. INTRODUCTION Generic name - Lesinurad Brand name – Zurampic
Class – uricosuric
Approved by FDA in – Dec 2015
Manufactured by : IRONWOOD PHARMS INC.
Therapeutic areas – Rheumatology
Specific treatment – Gout

3. INDICATIONS
ZURAMPIC is indicated in combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout.
It is used in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone.

4. MECHANISM OF ACTION
Lesinurad inhibited the function of two apical transporters in kidney responsible for uric acid reabsorption.
Uric acid transporter 1 (URAT1) and organic anion transporter 4 (OAT4).

5. MECHANISM OF ACTION
URAT1 is responsible for the majority of the reabsorption of filtered uric acid from the renal tubular lumen.
OAT4 is a uric acid transporter associated
with hyperuricemia.

6. PHARMACOKINETICS AND PHARMACODYNAMICS
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. PHARMACOKINETICS AND PHARMACODYNAMICS
It is metabolized mainly by the liver enzyme CYP2C9, predominantly to a hydroxylated substance called “M3” and an epoxide “M3c”.
The absolute bioavailability of lesinurad is approximately 100%.
Lesinurad is rapidly absorbed after oral administration.
The elimination half-life (t½) of lesinurad was approximately 5 hours.

8. PHARMACOKINETICS AND PHARMACODYNAMICS
Lesinurad undergoes oxidative metabolism mainly via the polymorphic cytochrome P450 CYP2C9 enzyme.
Metabolites are not known to contribute to the uric acid lowering effects of ZURAMPIC.
Lesinurad is excreted via the urine (nearly 63%) and feces (nearly 32%).

9. DOSES AND ADMINISTRATION
ZURAMPIC tablets are for oral use.
ZURAMPIC is recommended orally at 200 mg once daily.
It should be taken, in the morning with food and water.
Use of ZURAMPIC is not recommended for patients taking daily doses of allopurinol less than 300mg.

10. DOSES AND ADMINISTRATION
ZURAMPIC Tablets, 200 mg are blue in color, oval shaped, debossed with “LES200” and are supplied as follows:
Bottle of 5 tablets
Bottle of 30 tablets
Bottle of 90 tablets SOURCE: google images

11. USAGE & DOSES
ZURAMPIC tablets are for oral use and should be co-administered with a xanthine oxidase inhibitor, including allopurinol or febuxostat.
ZURAMPIC is recommended at 200 mg once daily. This is also the maximum daily dose.
ZURAMPIC should be taken by mouth, in the morning with food and water.

12. DOSE ADJUSTMENT IN RENAL FALIURE
No dose adjustment is needed in patients with mild or moderate renal impairment (CLcr of 45 mL/min or greater).
ZURAMPIC should not be initiated in patients with an CLcr less than 45 mL/min.
Assessment of renal function is recommended prior to initiation of ZURAMPIC therapy and periodically thereafter .

13. DOSE ADJUSTMENT IN HEPATIC FALIURE
No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B).
Lesinurad has not been studied in patients with severe hepatic impairment and is therefore not recommended.

14. DRUG INTERACTIONS
Lesinurad exposure is increased when ZURAMPIC is co-administered with inhibitors of CYP2C9 (fluconazole, amiodarone).
Lesinurad exposure is decreased when co-administered with moderate inducers of CYP2C9 (eg, rifampin).
Inducers may decrease the therapeutic effect of ZURAMPIC.

15. DRUG INTERACTIONS
Aspirin at doses higher than 325 mg per day may decrease the efficacy of ZURAMPIC in combination with allopurinol.
Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking ZURAMPIC.

16. DRUG INTERACTIONS
No teratogenicity or effects on fetal development were observed.
There is no information regarding the presence of ZURAMPIC in human milk, the effects on the breastfed infant, or the effects on milk production.
ZURAMPIC was studied in healthy subjects given single doses up to 1600 mg without evidence of dose-limiting toxicities.

17. ADVERSE DRUG REACTIONS
1.Renal Events:
Treatment with ZURAMPIC 200 mg in combination with a xanthine oxidase inhibitor was associated with an increased incidence of serum creatinine elevations.
Most of which were reversible.

18. ADVERSE DRUG REACTIONS
2. Cardiovascular Events:
In clinical trials, major adverse cardiovascular events (cardiovascular deaths, non-fatal myocardial infarctions) were observed with ZURAMPIC.
However a causal relationship with ZURAMPIC has not been established.

19. CONTRAINDICATIONS
Severe renal impairment (CLcr less than 30 mL/min), end stage renal disease, kidney transplant recipients, or patients on dialysis.
Tumor lysis syndrome.
Lesch-Nyhan syndrome.

20. WARNING AND PRECAUTIONS
ZURAMPIC should not be initiated in patients with an CLcr less than 45 mL/min.
Valproic acid may interfere with metabolism of lesinurad.

21. EDGE OVER EXISTING URICOSURICS?
Many drugs such as tenofovir, reverse transcriptase inhibitors depend on OAT1 and OAT3 for clearance through kidneys.
Existing urate lowering drugs such as probenecid inhibit OAT1 and OAT3 thus posing a significant problem of drug–drug interactions.
Lesinurad devoid of interaction with OAT1 or OAT3, is a major breakthrough in solving this hurdle of clinically relevant drug–drug interactions

22. EDGE OVER EXISTING URICOSURICS?
No unfavorable pharmacokinetic interaction or interference with urinary excretion exists between lesinurad and XOIs such as allopurinol and febuxostat.
Continued use of allopurinol at suboptimal doses in patients with renal insufficiency could worsen renal failure, or sometimes may precipitate fatal hypersensitivity syndrome.

23. Combining lesinurad at a fixed dose of 200 mg/day with XOIs helps in controlling hyperuricemia more effectively.
Combination with allopurinol 300mg is made .

24. What is the most important information I should know about ZURAMPIC?
Some patients taking ZURAMPIC may have kidney problems such as sudden decrease in kidney function (acute kidney failure).
This is more common when patient take ZURAMPIC without any xanthine oxidase inhibitor.
One should always take ZURAMPIC with a xanthine oxidase inhibitor( allopurinol).

25. Source:

26. FOR MORE INFORMATION ON ZURAMPIC
Reference id:

27. THANK YOU