The development of Zurampic®(Lesinurad), a first selective uric acid resorption inhibitor to treat gout
Summary: Gout is the most common inflammatory arthropathy in the western world, which is caused by the excess accumulation of uric acid in the blood instead of normally excreting by kidney. Millions of people suffer from this kind of arthritis with an attack of sudden burning pain, stiffness, and swelling in a joint(usually a big toe). However, the current treatment for gout is far from adequate, because controlling the acute episode has been the prior management for decades by using nonsteroidal antinflammatory drugs (NSAIDs), colchicine or glucocorticoids. With a deeper understanding of gout pathophysiology these years, urate lowing has …show more content…
CLEAR1 and CLEAR2 are very important because it have evaluated the efficacy and safety of a once daily oral dose of Zurampic(200 mg or 400 mg) in combination with allopurinol compared to allopurinol alone.[11] 402 patients were enrolled in CLEAR1 study to compare the proportion of patients who have achieved the goal of reducing the serum uric acid level(sUA) below 6mg/dl after 12 months treatment of 200 mg Zurampic plus allopurinol or same dose of placebo plus allopurinol. The primary endpoint(shown as Fig 2) indicates that there is a significant achievement of the group with 200 mg Zurampic plus allopurinol treatment, and Zurampic even doubled the number of patients who achieved sUA target <5 mg/dL whatever this function is significant or not. Furthermore, for the secondary endpoint, 200 mg or 400 mg Zurampic in combination with febuxostat did help reduce the total tophus area by month 12 comparing with febuxostat alone although the difference in the proportion of subjects achieving a complete resolution of at least one tophus by month 12 is not statistically significant(shown as Fig …show more content…
Since the transporters expressed in the kidney and liver play an important role in the process of inhibiting urate absorption, a phase I study was conducted to evaluate the drug-drug interaction between Zurampic(lesinurad) and atorvastatin, metformin, or furosemide(substrates of major liver or kidney transporters) in clinical studies by recruiting only healthy male subjects(ages 18–65 years; body mass index 18–32 kg/m2). 28 subjects received 40 mg atorvastatin with or without 200 mg or 400 mg lesinurad; 12 subjects received 850 mg metformin with or without 400 mg lesinurad; 11 subjects received 40 mg furosemide with or without 400 mg lesinurad.[15] The result has shown that there is not a statistically drug and drug interaction between lesinurad and substrates of major liver or kidney transporters(atrovastatin, metformin, furosemide), even though the treatment with lesinurad(200 mg or 400 mg)would alter the maximum concentration(Cmax)and area under the concentration–time curve (AUC) of atrovastatin and furosemide, lesinurad would not change the renal clearance and diuretic activity of these drugs.[15] However, lesinurad definitely has some interaction with drugs of CYP2C9 inhibitors(such as fluconazole) or inducers(such as rifampin), which would influence the metabolic process of lesinurad. Besides the class of CYP2C9, the
Summary: Gout is the most common inflammatory arthropathy in the western world, which is caused by the excess accumulation of uric acid in the blood instead of normally excreting by kidney. Millions of people suffer from this kind of arthritis with an attack of sudden burning pain, stiffness, and swelling in a joint(usually a big toe). However, the current treatment for gout is far from adequate, because controlling the acute episode has been the prior management for decades by using nonsteroidal antinflammatory drugs (NSAIDs), colchicine or glucocorticoids. With a deeper understanding of gout pathophysiology these years, urate lowing has …show more content…
CLEAR1 and CLEAR2 are very important because it have evaluated the efficacy and safety of a once daily oral dose of Zurampic(200 mg or 400 mg) in combination with allopurinol compared to allopurinol alone.[11] 402 patients were enrolled in CLEAR1 study to compare the proportion of patients who have achieved the goal of reducing the serum uric acid level(sUA) below 6mg/dl after 12 months treatment of 200 mg Zurampic plus allopurinol or same dose of placebo plus allopurinol. The primary endpoint(shown as Fig 2) indicates that there is a significant achievement of the group with 200 mg Zurampic plus allopurinol treatment, and Zurampic even doubled the number of patients who achieved sUA target <5 mg/dL whatever this function is significant or not. Furthermore, for the secondary endpoint, 200 mg or 400 mg Zurampic in combination with febuxostat did help reduce the total tophus area by month 12 comparing with febuxostat alone although the difference in the proportion of subjects achieving a complete resolution of at least one tophus by month 12 is not statistically significant(shown as Fig …show more content…
Since the transporters expressed in the kidney and liver play an important role in the process of inhibiting urate absorption, a phase I study was conducted to evaluate the drug-drug interaction between Zurampic(lesinurad) and atorvastatin, metformin, or furosemide(substrates of major liver or kidney transporters) in clinical studies by recruiting only healthy male subjects(ages 18–65 years; body mass index 18–32 kg/m2). 28 subjects received 40 mg atorvastatin with or without 200 mg or 400 mg lesinurad; 12 subjects received 850 mg metformin with or without 400 mg lesinurad; 11 subjects received 40 mg furosemide with or without 400 mg lesinurad.[15] The result has shown that there is not a statistically drug and drug interaction between lesinurad and substrates of major liver or kidney transporters(atrovastatin, metformin, furosemide), even though the treatment with lesinurad(200 mg or 400 mg)would alter the maximum concentration(Cmax)and area under the concentration–time curve (AUC) of atrovastatin and furosemide, lesinurad would not change the renal clearance and diuretic activity of these drugs.[15] However, lesinurad definitely has some interaction with drugs of CYP2C9 inhibitors(such as fluconazole) or inducers(such as rifampin), which would influence the metabolic process of lesinurad. Besides the class of CYP2C9, the