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Zancong Shen - One of the best experts on this subject based on the ideXlab platform.

  • metabolism and disposition of Lesinurad a uric acid reabsorption inhibitor in humans
    Xenobiotica, 2019
    Co-Authors: Vishal Shah, Chun Yang, Zancong Shen, David M. Wilson, Bradley M. Kerr, Kathy Tieu, Jesse Hall, Michael Gillen, Caroline A. Lee
    Abstract:

    The objectives of this study were to determine the absolute bioavailability of Lesinurad and to characterized its disposition in humans. The oral bioavailability assessment was performed using a clinical design of simultaneous dosing of a therapeutic oral dose of Lesinurad with an intravenous infusion of [14C]Lesinurad microdose. The bioavailability of Lesinurad was determined to be 100%. The disposition of Lesinurad in humans involves hepatic oxidation and renal elimination following administration of oral [14C]Lesinurad dose. Metabolism of Lesinurad occurred post-systemically with low circulating levels of metabolites <3% of total radioactivity as 74.2% of total radioactivity was attributed to Lesinurad. In vitro metabolism studies identified CYP2C9 as the predominant isoform, and summation of metabolites indicated that it was responsible for ∼50% of metabolism.

  • effects of food and antacids on pharmacokinetics and pharmacodynamics of Lesinurad a selective urate reabsorption inhibitor
    Clinical pharmacology in drug development, 2019
    Co-Authors: Zancong Shen, David M. Wilson, Caroline A. Lee, Shakti Valdez, Xiaojuan Yang, Talia Flanagan, Michael Gillen
    Abstract:

    Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on Lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000 mg calcium carbonate or 1600 mg magnesium hydroxide/1600 mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400 mg oral Lesinurad. Study 2 evaluated low doses of antacids (1250 mg calcium carbonate or 800 mg magnesium hydroxide/800 mg aluminum hydroxide) on the PK and PD of 400 mg Lesinurad. Food did not alter the plasma AUC of Lesinurad and only reduced its Cmax by 18%. In the fasted conditions, high-dose calcium carbonate reduced the Cmax and AUC of Lesinurad by 54% and 38%, respectively, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced Cmax and AUC by 36% and 31%, respectively. Food enhanced the maximum serum urate (sUA)-lowering effect of Lesinurad by approximately 20% despite reducing the Cmax of Lesinurad. High-dose calcium carbonate decreased the urate-lowering effect approximately 20% in the first 6 hours, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced the effect by 26%. Low-dose calcium carbonate or magnesium hydroxide/aluminum hydroxide in the presence of food did not significantly affect plasma Lesinurad Cmax and AUC or the sUA lowering and renal handling of uric acid. In summary, study results suggest food did not meaningfully alter Lesinurad PK and PD. High doses of antacids reduced Lesinurad AUC up to 40% and reduced the Lesinurad uric acid-lowering effect.

  • Lesinurad evaluation of pharmacokinetic and pharmacodynamic interactions with warfarin in healthy volunteers
    Clinical pharmacology in drug development, 2019
    Co-Authors: Zancong Shen, David M. Wilson, Caroline A. Lee, Bradley M. Kerr, Kathleen Wallach, Shakti Valdez, Michael Gillen
    Abstract:

    Lesinurad is a selective uric acid reabsorption inhibitor approved for use in combination with xanthine oxidase inhibitors for the treatment of hyperuricemia associated with gout. In vitro, Lesinurad was shown to be a weak inhibitor of cytochrome P450 (CYP)2C9 and a weak inducer of CYP3A4. Warfarin is a widely prescribed oral coumarin-based anticoagulant commonly prescribed in gout patients. In an open-label clinical study in healthy adult male subjects, the effects of multiple daily doses of 400 mg Lesinurad on the pharmacokinetics and pharmacodynamics of a single dose of 25 mg warfarin (racemic mixture of R- and S- enantiomers) were evaluated. Lesinurad had no effect on the absorption or the exposure (area under the concentration-time curve [AUC] and peak concentration) of the more active S-warfarin enantiomer. A slight reduction (19%) in overall plasma exposure (AUC) was observed for the R-warfarin enantiomer. Lesinurad had no meaningful clinical impact on anticoagulation activity as measured by prothrombin time, activated partial thromboplastin time, and international normalized ratio of prothrombin time and Factor VII clotting activity. Overall, the administration of warfarin in the presence of multiple-dose Lesinurad was devoid of clinically significant drug-drug interaction.

  • Characterization of Stereoselective Metabolism, Inhibitory Effect on Uric Acid Uptake Transporters, and Pharmacokinetics of Lesinurad Atropisomers.
    Drug metabolism and disposition: the biological fate of chemicals, 2018
    Co-Authors: Chun Yang, Dongmei Zhou, Zancong Shen, David M. Wilson, Matthew Renner, Jeffrey N. Miner, Jean-luc Girardet, Caroline A. Lee
    Abstract:

    Lesinurad [Zurampic; 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)], a selective inhibitor of uric acid reabsorption transporters approved for the treatment of gout, is a racemate of two atropisomers. The objective of this investigation was to evaluate the stereoselectivity of metabolism, the inhibitory potency on kidney uric acid reabsorption transporters (URAT1 and OAT4), and the clinical pharmacokinetics of the Lesinurad atropisomers. Incubations with human liver microsomes (HLM), recombinant CYP2C9, and recombinant CYP3A4 were carried out to characterize the stereoselective formation of three metabolites: M3 (hydroxylation), M4 (a dihydrodiol metabolite), and M6 (S-dealkylation). The formation of M3 in HLM with atropisomer 1 was approximately twice as much as that with atropisomer 2, whereas formation of M4 with atropisomer 1 was 8- to 12-fold greater than that with atropisomer 2. There were no significant differences in the plasma protein binding among Lesinurad and the atropisomers. Following oral administration of 400 mg Lesinurad once daily for 14 days to healthy human volunteers, the systemic exposure (Cmax at steady state and area under the concentration-time curve from time zero to the time of dosing interval) of atropisomer 1 was approximately 30% lower than that of atropisomer 2, whereas renal clearance was similar. In vitro cell-based assays using HEK293 stable cells expressing URAT1 and OAT4 demonstrated that atropisomer 2 was approximately 4-fold more potent against URAT1 than atropisomer 1 and equally active against OAT4. In conclusion, Lesinurad atropisomers showed stereoselectivity in clinical pharmacokinetics, metabolism, and inhibitory potency against URAT1.

  • the effect of Lesinurad in combination with allopurinol on serum uric acid levels in patients with gout
    The Journal of Clinical Pharmacology, 2018
    Co-Authors: Scott Baumgartner, Zancong Shen, Bradley M. Kerr, Kimberly Manhard, Litain Yeh, Barry D Quart
    Abstract:

    The objective of the study was to evaluate the effect of Lesinurad, a selective uric acid uptake inhibitor, alone and in combination with the xanthine oxidase inhibitor allopurinol, on serum uric acid and urinary urate excretion in patients with gout and hyperuricemia. A phase 1b, multicenter, open-label, multiple-dose study was carried out in patients with gout with serum uric acid ≥8 mg/dL following washout of urate-lowering therapy. Patients were treated with allopurinol 300 mg/day alone in week 1; Lesinurad 400 or 600 mg/day was added in week 2, followed by Lesinurad 400 or 600 mg/day alone in week 3. Serum uric acid and urine uric acid were evaluated each week. Safety was assessed throughout the study. Lesinurad 400 or 600 mg/day added to allopurinol 300 mg/day reduced serum uric acid by 60% and 72%, respectively, versus allopurinol alone (37%) or Lesinurad 400 mg/day (44%) or 600 mg/day (47%) alone. A 100% response rate of serum uric acid <6 mg/dL was achieved by all combinations (serum uric acid <5 mg/dL by 50%-90%). Mean 24-hour urate excretion compared with baseline was -35% with allopurinol, +36% and +56.5% with Lesinurad 400 mg/day and 600 mg/day, respectively, and -11.6% and -7.1% with the respective combination therapies. Treatments were well tolerated. In this phase 1 trial, Lesinurad added to allopurinol resulted in greater serum uric acid reduction than did allopurinol or Lesinurad monotherapy.

Michael Gillen - One of the best experts on this subject based on the ideXlab platform.

  • effects of food and antacids on pharmacokinetics and pharmacodynamics of Lesinurad a selective urate reabsorption inhibitor
    Clinical pharmacology in drug development, 2019
    Co-Authors: Zancong Shen, David M. Wilson, Caroline A. Lee, Shakti Valdez, Xiaojuan Yang, Talia Flanagan, Michael Gillen
    Abstract:

    Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on Lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000 mg calcium carbonate or 1600 mg magnesium hydroxide/1600 mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400 mg oral Lesinurad. Study 2 evaluated low doses of antacids (1250 mg calcium carbonate or 800 mg magnesium hydroxide/800 mg aluminum hydroxide) on the PK and PD of 400 mg Lesinurad. Food did not alter the plasma AUC of Lesinurad and only reduced its Cmax by 18%. In the fasted conditions, high-dose calcium carbonate reduced the Cmax and AUC of Lesinurad by 54% and 38%, respectively, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced Cmax and AUC by 36% and 31%, respectively. Food enhanced the maximum serum urate (sUA)-lowering effect of Lesinurad by approximately 20% despite reducing the Cmax of Lesinurad. High-dose calcium carbonate decreased the urate-lowering effect approximately 20% in the first 6 hours, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced the effect by 26%. Low-dose calcium carbonate or magnesium hydroxide/aluminum hydroxide in the presence of food did not significantly affect plasma Lesinurad Cmax and AUC or the sUA lowering and renal handling of uric acid. In summary, study results suggest food did not meaningfully alter Lesinurad PK and PD. High doses of antacids reduced Lesinurad AUC up to 40% and reduced the Lesinurad uric acid-lowering effect.

  • metabolism and disposition of Lesinurad a uric acid reabsorption inhibitor in humans
    Xenobiotica, 2019
    Co-Authors: Vishal Shah, Chun Yang, Zancong Shen, David M. Wilson, Bradley M. Kerr, Kathy Tieu, Jesse Hall, Michael Gillen, Caroline A. Lee
    Abstract:

    The objectives of this study were to determine the absolute bioavailability of Lesinurad and to characterized its disposition in humans. The oral bioavailability assessment was performed using a clinical design of simultaneous dosing of a therapeutic oral dose of Lesinurad with an intravenous infusion of [14C]Lesinurad microdose. The bioavailability of Lesinurad was determined to be 100%. The disposition of Lesinurad in humans involves hepatic oxidation and renal elimination following administration of oral [14C]Lesinurad dose. Metabolism of Lesinurad occurred post-systemically with low circulating levels of metabolites <3% of total radioactivity as 74.2% of total radioactivity was attributed to Lesinurad. In vitro metabolism studies identified CYP2C9 as the predominant isoform, and summation of metabolites indicated that it was responsible for ∼50% of metabolism.

  • Lesinurad evaluation of pharmacokinetic and pharmacodynamic interactions with warfarin in healthy volunteers
    Clinical pharmacology in drug development, 2019
    Co-Authors: Zancong Shen, David M. Wilson, Caroline A. Lee, Bradley M. Kerr, Kathleen Wallach, Shakti Valdez, Michael Gillen
    Abstract:

    Lesinurad is a selective uric acid reabsorption inhibitor approved for use in combination with xanthine oxidase inhibitors for the treatment of hyperuricemia associated with gout. In vitro, Lesinurad was shown to be a weak inhibitor of cytochrome P450 (CYP)2C9 and a weak inducer of CYP3A4. Warfarin is a widely prescribed oral coumarin-based anticoagulant commonly prescribed in gout patients. In an open-label clinical study in healthy adult male subjects, the effects of multiple daily doses of 400 mg Lesinurad on the pharmacokinetics and pharmacodynamics of a single dose of 25 mg warfarin (racemic mixture of R- and S- enantiomers) were evaluated. Lesinurad had no effect on the absorption or the exposure (area under the concentration-time curve [AUC] and peak concentration) of the more active S-warfarin enantiomer. A slight reduction (19%) in overall plasma exposure (AUC) was observed for the R-warfarin enantiomer. Lesinurad had no meaningful clinical impact on anticoagulation activity as measured by prothrombin time, activated partial thromboplastin time, and international normalized ratio of prothrombin time and Factor VII clotting activity. Overall, the administration of warfarin in the presence of multiple-dose Lesinurad was devoid of clinically significant drug-drug interaction.

  • Metabolism and disposition of Lesinurad, a uric acid reabsorption inhibitor, in humans
    2018
    Co-Authors: Vishal Shah, Chun Yang, Zancong Shen, David M. Wilson, Bradley M. Kerr, Kathy Tieu, Jesse Hall, Michael Gillen, Caroline A. Lee
    Abstract:

    The objectives of this study were to determine the absolute bioavailability of Lesinurad and to characterized its disposition in humans.The oral bioavailability assessment was performed using a clinical design of simultaneous dosing of a therapeutic oral dose of Lesinurad with an intravenous infusion of [14C]Lesinurad microdose. The bioavailability of Lesinurad was determined to be 100%.The disposition of Lesinurad in humans involves hepatic oxidation and renal elimination following administration of oral [14C]Lesinurad dose.Metabolism of Lesinurad occurred post-systemically with low circulating levels of metabolites

  • evaluation of pharmacokinetic interactions between Lesinurad a new selective urate reabsorption inhibitor and cyp enzyme substrates sildenafil amlodipine tolbutamide and repaglinide
    Clinical pharmacology in drug development, 2017
    Co-Authors: Michael Gillen, Chun Yang, David M. Wilson, Caroline A. Lee, Bradley M. Kerr, Shakti Valdez, Zancong Shen
    Abstract:

    Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. In vitro assays indicate that Lesinurad is an inducer of CYPs in the order CYP3A > CYP2C8 > CYP2C9 > CYP2C19 > CYP2B6 and an inhibitor of CYP2C8 and CYP2C9. To investigate the drug interaction potential of Lesinurad, clinical drug interaction studies were conducted. Open-label studies in volunteers investigated the effects of single-/multiple-dose Lesinurad on the pharmacokinetics of sildenafil and amlodipine (CYP3A4 induction), tolbutamide (CYP2C9 inhibition/induction), and repaglinide (CYP2C8 inhibition/induction). There was no apparent induction of CYP2C8 and CYP2C9 following repeated Lesinurad administration, although no inhibition of CYP2C9 and modest inhibition of CYP2C8 were observed following single-dose Lesinurad. Consistent with in vitro observations, Lesinurad (200 mg once daily) was an inducer of CYP3A based on the effects on sildenafil exposure. Sildenafil exposure decreased by approximately 34% for Cmax and AUC when administered with multiple-dose Lesinurad 200 mg and allopurinol 300 mg, relative to sildenafil alone. During Lesinurad therapy, the possibility of reduced efficacy of concomitant drugs that are CYP3A substrates should be considered and their efficacy monitored because of induction of CYP3A by Lesinurad.

Scott Baumgartner - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety during extended treatment of Lesinurad in combination with febuxostat in patients with tophaceous gout crystal extension study
    Arthritis Research & Therapy, 2019
    Co-Authors: Nicola Dalbeth, Maple Fung, Robert Terkeltaub, Scott Baumgartner, Graeme Jones, Dinesh Khanna, Fernando Perezruiz
    Abstract:

    In gout, long-term urate-lowering therapy (ULT) promotes dissolution of tissue urate crystal deposits. However, no studies using combined xanthine oxidase inhibition and uricosuric ULT have focused on clinical outcomes or adverse events (AEs) beyond 12 months of therapy. Our objective in the present study was to examine efficacy and long-term safety in patients with tophaceous gout receiving febuxostat plus Lesinurad as combination therapy. Patients receiving combined Lesinurad and febuxostat in the 12-month core CRYSTAL study continued at the same doses in the extension study (“200CONT”, “400CONT”), whereas those receiving only febuxostat 80 mg were randomized to Lesinurad 200 or 400 mg with febuxostat (“200CROSS”, “400CROSS”). The primary endpoint was the proportion of patients experiencing complete resolution (CR) of at least one target tophus by extension month (EM) 12. The key secondary endpoint was mean rate of gout flares requiring treatment from the end of EM 2 to the end of EM 12. Secondary endpoints included reduction in the sum of areas for all target tophi. Safety assessments included AEs and laboratory data for the entire extension study (median length of Lesinurad exposure, 800 days). Of 235 patients completing the core study, 196 (83.4%) enrolled in the extension: 200CONT (n = 64), 200CROSS (n = 33), 400CONT (n = 65), and 400CROSS (n = 34). At EM 12, 59.6%, 43.5%, 66.7%, and 50.0% of patients, respectively, had CR of at least one target tophus. The sum of areas for all target tophi was reduced by 76.4%, 58.1%, 77.5%, and 62.8%, respectively. The adjusted mean (SE) rates of gout flares requiring treatment from the end of EM 2 to the end of EM 12 were 0.6 (0.19), 1.3 (0.48), 0.2 (0.08), and 1.9 (0.93), respectively. Target sUA < 5.0 mg/dl was achieved by 77.1%, 79.2%, 88.5%, and 71.4% of patients, respectively. Exposure-adjusted incidence rates of treatment-emergent adverse events (TEAEs) and renal-related TEAEs in the core study were not increased with prolonged Lesinurad exposure in the extension study. Patients receiving Lesinurad plus febuxostat therapy for 2 years continued to be at sUA target. Patients exhibited a progressive increase in CR of at least one target tophus, progressive reduction in tophus size, and reduction of gout flares requiring treatment over the second year, with AEs consistent with those observed in the core study. ClinicalTrials.gov , NCT01510769 . Registered on 13 January 2012.

  • Additional file 1: of Efficacy and safety during extended treatment of Lesinurad in combination with febuxostat in patients with tophaceous gout: CRYSTAL extension study
    2019
    Co-Authors: Nicola Dalbeth, Maple Fung, Robert Terkeltaub, Scott Baumgartner, Graeme Jones, Dinesh Khanna, Fernando Perez-ruiz
    Abstract:

    Table S1. Renal-related and kidney stone TEAEs. Table S2. TEAEs with > 5% of patients in either total treatment group during the extension study (safety population). CONT Continuation of Lesinurad treatment, CROSS Crossover from core study placebo to Lesinurad treatment. Figure S1. Patient disposition. *Subjects terminated any time during the study. (DOCX 88 kb

  • integrated safety studies of the urate reabsorption inhibitor Lesinurad in treatment of gout
    Rheumatology, 2019
    Co-Authors: Robert Terkeltaub, Scott Baumgartner, Kenneth G Saag, Ritu Valiyil, Bruce Schechter, David S Goldfarb, Michael H Pillinger, Diana Jalal, William B White
    Abstract:

    Author(s): Terkeltaub, Robert; Saag, Kenneth G; Goldfarb, David S; Baumgartner, Scott; Schechter, Bruce M; Valiyil, Ritu; Jalal, Diana; Pillinger, Michael; White, William B | Abstract: Objective:Lesinurad (LESU) is a selective urate reabsorption inhibitor approved at 200 mg daily for use with a xanthine oxidase inhibitor (XOI) to treat hyperuricaemia in gout patients failing to achieve target serum urate on XOI. The aim of the study was to investigate the long-term safety of LESU + XOI therapy. Methods:Safety data were pooled from three 12-month phase III (core) trials evaluating LESU 200 and 400 mg/day combined with an XOI (LESU200+XOI and LESU400+XOI), and two 12-month extension studies using descriptive statistics. To adjust for treatment duration, treatment-emergent adverse events (TEAEs) were expressed as exposure-adjusted incidence rates (patients with events per 100 person-years). Results:In the core studies, exposure-adjusted incidence rates for total and total renal-related TEAEs were comparable for XOI alone and LESU200+XOI but higher with LESU400+XOI. Exposure-adjusted incidence rates for serum creatinine (sCr) elevations ⩾1.5×baseline were 2.9, 7.3 and 18.7, respectively. Resolution (sCr ⩽1.2×baseline) occurred in 75-90% of all events, with 66-75% occurring without any study medication interruption. Major adverse cardiovascular events were 3, 4 and 9 with XOI, LESU200+XOI and LESU400+XOI, respectively. Longer exposure in core+extension studies did not increase rates for any safety signals. Conclusion:At the approved dose of 200 mg once-daily combined with an XOI, LESU did not increase renal, cardiovascular or other adverse events compared with XOI alone, except for sCr elevations. With extended exposure in the core+extension studies, the safety profile was consistent with that observed in the core studies, and no new safety concerns were identified.

  • the effect of Lesinurad in combination with allopurinol on serum uric acid levels in patients with gout
    The Journal of Clinical Pharmacology, 2018
    Co-Authors: Scott Baumgartner, Zancong Shen, Bradley M. Kerr, Kimberly Manhard, Litain Yeh, Barry D Quart
    Abstract:

    The objective of the study was to evaluate the effect of Lesinurad, a selective uric acid uptake inhibitor, alone and in combination with the xanthine oxidase inhibitor allopurinol, on serum uric acid and urinary urate excretion in patients with gout and hyperuricemia. A phase 1b, multicenter, open-label, multiple-dose study was carried out in patients with gout with serum uric acid ≥8 mg/dL following washout of urate-lowering therapy. Patients were treated with allopurinol 300 mg/day alone in week 1; Lesinurad 400 or 600 mg/day was added in week 2, followed by Lesinurad 400 or 600 mg/day alone in week 3. Serum uric acid and urine uric acid were evaluated each week. Safety was assessed throughout the study. Lesinurad 400 or 600 mg/day added to allopurinol 300 mg/day reduced serum uric acid by 60% and 72%, respectively, versus allopurinol alone (37%) or Lesinurad 400 mg/day (44%) or 600 mg/day (47%) alone. A 100% response rate of serum uric acid <6 mg/dL was achieved by all combinations (serum uric acid <5 mg/dL by 50%-90%). Mean 24-hour urate excretion compared with baseline was -35% with allopurinol, +36% and +56.5% with Lesinurad 400 mg/day and 600 mg/day, respectively, and -11.6% and -7.1% with the respective combination therapies. Treatments were well tolerated. In this phase 1 trial, Lesinurad added to allopurinol resulted in greater serum uric acid reduction than did allopurinol or Lesinurad monotherapy.

  • Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor a 6 month phase 3 clinical trial and extension study
    Rheumatology, 2017
    Co-Authors: Anne-kathrin Tausche, C. Storgard, Maple Fung, Nicola Dalbeth, R Alten, J Kopicko, Scott Adler, N Bhakta, Scott Baumgartner, Kenneth G Saag
    Abstract:

    Objective: To investigate the efficacy and safety of Lesinurad, a selective uric acid reabsorption inhibitor, in a 6 month, phase 3 clinical trial and extension study. Methods: Patients with gout who cannot take a xanthine oxidase inhibitor (XOI) and have serum uric acid (sUA) ⩾6.5 mg/dl were randomized to receive oral Lesinurad (400 mg daily) or placebo. The primary endpoint was the proportion of patients with sUA <6.0 mg/dl at month 6. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory data. Patients who completed the study were eligible for an open-label, uncontrolled extension study of Lesinurad 400 mg monotherapy. Results: Patients (n = 214) were primarily white males (mean age 54.4 years; gout duration 11.2 years). Significantly more patients achieved the primary endpoint with Lesinurad than placebo (29.9 vs 1.9%; P < 0.0001). Overall TEAE rates were higher with Lesinurad (77.6 vs 65.4%); renal-related TEAEs (17.8%), renal-related serious TEAEs (4.7%) and serum creatinine elevations (1.5 times baseline, 24.3%) occurred only with Lesinurad. A total of 143 patients (65 Lesinurad, 78 placebo) enrolled in the extension study. Treatment with Lesinurad 400 mg resulted in rapid and sustained sUA lowering that persisted for up to 18 months before the study was terminated prematurely. No new safety findings were observed in the extension. Conclusion: In patients with gout and intolerance/contraindication to XOIs, Lesinurad 400 mg monotherapy demonstrated superior sUA lowering compared with placebo, with sustained effects for up to 18 months. Due to a high incidence of serum creatinine elevations and renal-related adverse events, including serious adverse events with Lesinurad 400 mg, Lesinurad should not be used as monotherapy. Trial registration: ClinicalTrials.gov (http://clinincaltrials.gov), NCT01508702.

C. Storgard - One of the best experts on this subject based on the ideXlab platform.

  • Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor a 6 month phase 3 clinical trial and extension study
    Rheumatology, 2017
    Co-Authors: Anne-kathrin Tausche, C. Storgard, Maple Fung, Nicola Dalbeth, R Alten, J Kopicko, Scott Adler, N Bhakta, Scott Baumgartner, Kenneth G Saag
    Abstract:

    Objective: To investigate the efficacy and safety of Lesinurad, a selective uric acid reabsorption inhibitor, in a 6 month, phase 3 clinical trial and extension study. Methods: Patients with gout who cannot take a xanthine oxidase inhibitor (XOI) and have serum uric acid (sUA) ⩾6.5 mg/dl were randomized to receive oral Lesinurad (400 mg daily) or placebo. The primary endpoint was the proportion of patients with sUA <6.0 mg/dl at month 6. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory data. Patients who completed the study were eligible for an open-label, uncontrolled extension study of Lesinurad 400 mg monotherapy. Results: Patients (n = 214) were primarily white males (mean age 54.4 years; gout duration 11.2 years). Significantly more patients achieved the primary endpoint with Lesinurad than placebo (29.9 vs 1.9%; P < 0.0001). Overall TEAE rates were higher with Lesinurad (77.6 vs 65.4%); renal-related TEAEs (17.8%), renal-related serious TEAEs (4.7%) and serum creatinine elevations (1.5 times baseline, 24.3%) occurred only with Lesinurad. A total of 143 patients (65 Lesinurad, 78 placebo) enrolled in the extension study. Treatment with Lesinurad 400 mg resulted in rapid and sustained sUA lowering that persisted for up to 18 months before the study was terminated prematurely. No new safety findings were observed in the extension. Conclusion: In patients with gout and intolerance/contraindication to XOIs, Lesinurad 400 mg monotherapy demonstrated superior sUA lowering compared with placebo, with sustained effects for up to 18 months. Due to a high incidence of serum creatinine elevations and renal-related adverse events, including serious adverse events with Lesinurad 400 mg, Lesinurad should not be used as monotherapy. Trial registration: ClinicalTrials.gov (http://clinincaltrials.gov), NCT01508702.

  • Lesinurad a selective uric acid reabsorption inhibitor in combination with febuxostat in patients with tophaceous gout findings of a phase iii clinical trial
    Arthritis & Rheumatism, 2017
    Co-Authors: Nicola Dalbeth, C. Storgard, Maple Fung, Robert Terkeltaub, J Kopicko, Scott Adler, Graeme Jones, Dinesh Khanna, Nihar Bhakta, Scott Baumgartner
    Abstract:

    Author(s): Dalbeth, Nicola; Jones, Graeme; Terkeltaub, Robert; Khanna, Dinesh; Kopicko, Jeff; Bhakta, Nihar; Adler, Scott; Fung, Maple; Storgard, Chris; Baumgartner, Scott; Perez-Ruiz, Fernando | Abstract: To investigate the efficacy and safety of Lesinurad in combination with febuxostat in a 12-month phase III trial in patients with tophaceous gout.Patients with serum urate (UA) ≥8.0 mg/dl (≥6.0 mg/dl with urate-lowering therapy) and ≥1 measurable target tophus were given febuxostat 80 mg/day for 3 weeks before randomization to receive Lesinurad (200 or 400 mg daily) or placebo in addition to the febuxostat. The primary end point was the proportion of patients achieving a serum UA level of l5.0 mg/dl (month 6). The key secondary end point was the proportion of patients with complete resolution of ≥1 target tophus (month 12). Other end points included the percentage change in total target tophi area. Safety assessments included adverse events and laboratory data.Patients (n = 324) were predominantly male, with a mean age of 54.1 years. Significantly more patients achieved the serum UA target by month 6 with the addition of Lesinurad 400 mg (76.1%; P l 0.0001), but not 200 mg (56.6%; P = 0.13), to the febuxostat therapy as compared with febuxostat alone (46.8%). At all other time points, significantly more patients in the Lesinurad 200 mg group achieved the serum UA target. The number of patients with complete tophus resolution was not different between groups. Treatment with Lesinurad (200 mg and 400 mg) plus febuxostat reduced the total target tophi area as compared with febuxostat alone (50.1% and 52.9% versus 28.3%, respectively; P l 0.05). Safety was generally comparable with that of febuxostat alone, except for higher rates of predominantly reversible elevations in the serum creatinine level, particularly with Lesinurad 400 mg.Treatment with Lesinurad in combination with febuxostat demonstrated superior lowering of serum UA levels as compared with febuxostat alone, with clinically relevant added effects on tophi and an acceptable safety profile with Lesinurad 200 mg in patients with tophaceous gout warranting additional therapy.

  • 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
    Annals of the Rheumatic Diseases, 2017
    Co-Authors: Thomas Bardin, C. Storgard, Maple Fung, J Kopicko, Scott Adler, N Bhakta, Scott Baumgartner, Robert T Keenan, Puja P Khanna, Alexander So
    Abstract:

    Objectives Determine the efficacy and safety of daily Lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial. Methods Patients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of Results Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p Conclusion Lesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and Lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy. Trial registration number NCT01493531.

  • Lesinurad combined with allopurinol a randomized double blind placebo controlled study in gout patients with an inadequate response to standard of care allopurinol a us based study
    Arthritis & Rheumatism, 2017
    Co-Authors: Kenneth G Saag, C. Storgard, Maple Fung, J Kopicko, Scott Adler, N Bhakta, Scott Baumgartner, David Fitzpatrick, Michael Becker
    Abstract:

    Objective Lesinurad is a selective uric acid reabsorption inhibitor used for the treatment of gout in combination with a xanthine oxidase inhibitor. The Combining Lesinurad with Allopurinol Standard of Care in Inadequate Responders (CLEAR 1) study, a 12-month, multicenter, randomized, double-blind, placebo-controlled phase III trial, was conducted to investigate daily Lesinurad (200 mg or 400 mg orally) added to allopurinol versus placebo plus allopurinol in patients with serum urate (UA) levels above a target of <6.0 mg/dl. Methods Patients receiving ≥300 mg of allopurinol (≥200 mg in those with moderate renal impairment) who had serum UA levels ≥6.5 mg/dl at screening and ≥2 gout flares during the previous year were studied. The primary end point was the proportion of patients achieving a serum UA level of <6.0 mg/dl at month 6. Key secondary end points were the mean gout flare rate requiring treatment (months 7–12) and the proportions of patients with complete resolution of ≥1 target tophus (month 12). Safety assessments included adverse events and laboratory data. Results The study patients (n = 603) were predominantly male and had a mean ± SD age of 51.9 ± 11.3 years, a gout duration of 11.8 ± 9.4 years, a baseline serum UA level of 6.94 ± 1.27 mg/dl, and were receiving an allopurinol dosage of 306.6 ± 59.58 mg/day. Lesinurad at doses of 200 mg or 400 mg added to allopurinol therapy significantly increased the proportions of patients who achieved serum UA target levels by month 6 as compared with those receiving allopurinol alone (54.2%, 59.2%, and 27.9%, respectively, P < 0.0001). Lesinurad was not significantly superior to allopurinol alone in terms of the secondary end points: rates of gout flares and complete resolution of tophi. Lesinurad was generally well-tolerated; the safety profile of the 200-mg dose was comparable to that of allopurinol alone, except for higher incidences of predominantly reversible elevations of serum creatinine levels. Conclusion Lesinurad added to allopurinol provided benefit as compared with allopurinol alone in reducing serum UA levels and represents a new treatment option for patients needing additional urate-lowering therapy.

  • THU0537 Clinical Response of Tophus and Flares To Extended Use of Lesinurad in Combination with A Xanthine Oxidase Inhibitor in Patients with Gout
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Thomas Bardin, C. Storgard, Maple Fung, Robert Terkeltaub, J. Hu, Nicola Dalbeth, Fernando Perez-ruiz
    Abstract:

    Background Three randomized, double-blind, Phase III trials reported that greater proportions of patients treated with Lesinurad 200 mg (LESU200) or 400 mg (LESU400), combined with the xanthine oxidase inhibitor (XOI) allopurinol (ALLO; CLEAR 1 and 2) or febuxostat (FBX; CRYSTAL), achieved serum uric acid (sUA) targets at 6 months versus xanthine oxidase inhibitor (XOI) + placebo (PBO). Objectives To evaluate the impact of long-term treatment with Lesinurad + XOI on tophus and flares for at least 1 year and up to 2 years. Methods Patients completing 12 months in the core CLEAR and CRYSTAL studies could enroll in respective uncontrolled, open-label extension studies (NCT01808131; NCT01808144). Patients randomized to LESU200 + XOI or LESU400 + XOI in the core studies who continued on combination therapy in the extension studies were analyzed. Efficacy endpoints included: (1) proportions of patients with complete resolution (CR) of ≥1 target tophus (i.e. measurable tophus on hands/wrists and/or feet/ankles 5–20 mm in longest diameter), (2) percent reductions in the total area of all target tophi, and (3) proportions of patients experiencing gout flares requiring treatment (GFRT). Results A total of 239 (LESU200+ALLO) and 232 (LESU400+ALLO) patients continued in the CLEAR extension; 64 (LESU200+FBX) and 65 (LESU400+FBX) patients continued in the CRYSTAL extension. Proportions of patients with CR of ≥1 target tophus increased from end of core study (1 year) to 2 years: from 25.0% to 43.8% in LESU200+ALLO and 30.3% to 36.4% in LESU400+ALLO, and from 26.6% to 53.1% in LESU200+FBX and 35.4% to 58.5% in LESU400+FBX (LOCF). Percent reduction in the total area of all target tophi versus baseline changed from end of core study to 2 years: from 11.6% to 41.8% in LESU200+ALLO and 42.7% to 49.3% in LESU400+ALLO, and from 54.8% to 68.3% in LESU200+FBX and 58.6% to 72.4% in LESU400+FBX (LOCF). Proportions of subjects with a GFRT per month decreased during continued combination treatment in both extension studies (Figure). The proportions of patients with a GFRT during Months 1, 12, and 24 were, respectively, 16.3, 7.9, and 5.6 in LESU200+ALLO; 18.1, 6.9, and 3.0 in LESU400+ALLO; 26.6, 10.9, 6.3 in LESU200+FBX; and 36.9, 4.6, 1.9 in LESU400+FBX. Extended treatment with LESU + XOI did not result in increased exposure-adjusted incidence rates of adverse events (AEs), AEs leading to discontinuation of Lesinurad, serious AEs, or clinical laboratory abnormalities. Conclusions The CLEAR and CRYSTAL extension studies showed that patients treated with Lesinurad + XOI for up to 2 years exhibited continued increases in the rate of complete resolution of tophi and reduction in tophus area, as well as decreased rates of GFRT. Acknowledgement This study was funded by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and was funded by AstraZeneca. Disclosure of Interest T. Bardin Grant/research support from: Ipsen, Menarini., Consultant for: AstraZeneca, Ipsen, Menarini, Novartis, Savient, Sobi, Takeda, Cymabay., N. Dalbeth Grant/research support from: AstraZeneca, Fonterra, Novartis., Consultant for: AstraZeneca, Fonterra, Pfizer, Takeda, Crealta, Cymabay., Speakers bureau: AstraZeneca, Teijin., R. Terkeltaub Consultant for: Ardea Biosciences, AstraZeneca, Takeda, Relburn, REVIVE., C. Storgard Employee of: Ardea Biosciences, a member of the AstraZeneca Group., M. Fung Employee of: Ardea Biosciences, a member of the AstraZeneca Group., J. Hu Employee of: Ardea Biosciences, a member of the AstraZeneca Group., F. Perez-Ruiz Consultant for: AstraZeneca, Menarini, Pfizer., Speakers bureau: AstraZeneca, Menarini, Pfizer.

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  • efficacy and safety during extended treatment of Lesinurad in combination with febuxostat in patients with tophaceous gout crystal extension study
    Arthritis Research & Therapy, 2019
    Co-Authors: Nicola Dalbeth, Maple Fung, Robert Terkeltaub, Scott Baumgartner, Graeme Jones, Dinesh Khanna, Fernando Perezruiz
    Abstract:

    In gout, long-term urate-lowering therapy (ULT) promotes dissolution of tissue urate crystal deposits. However, no studies using combined xanthine oxidase inhibition and uricosuric ULT have focused on clinical outcomes or adverse events (AEs) beyond 12 months of therapy. Our objective in the present study was to examine efficacy and long-term safety in patients with tophaceous gout receiving febuxostat plus Lesinurad as combination therapy. Patients receiving combined Lesinurad and febuxostat in the 12-month core CRYSTAL study continued at the same doses in the extension study (“200CONT”, “400CONT”), whereas those receiving only febuxostat 80 mg were randomized to Lesinurad 200 or 400 mg with febuxostat (“200CROSS”, “400CROSS”). The primary endpoint was the proportion of patients experiencing complete resolution (CR) of at least one target tophus by extension month (EM) 12. The key secondary endpoint was mean rate of gout flares requiring treatment from the end of EM 2 to the end of EM 12. Secondary endpoints included reduction in the sum of areas for all target tophi. Safety assessments included AEs and laboratory data for the entire extension study (median length of Lesinurad exposure, 800 days). Of 235 patients completing the core study, 196 (83.4%) enrolled in the extension: 200CONT (n = 64), 200CROSS (n = 33), 400CONT (n = 65), and 400CROSS (n = 34). At EM 12, 59.6%, 43.5%, 66.7%, and 50.0% of patients, respectively, had CR of at least one target tophus. The sum of areas for all target tophi was reduced by 76.4%, 58.1%, 77.5%, and 62.8%, respectively. The adjusted mean (SE) rates of gout flares requiring treatment from the end of EM 2 to the end of EM 12 were 0.6 (0.19), 1.3 (0.48), 0.2 (0.08), and 1.9 (0.93), respectively. Target sUA < 5.0 mg/dl was achieved by 77.1%, 79.2%, 88.5%, and 71.4% of patients, respectively. Exposure-adjusted incidence rates of treatment-emergent adverse events (TEAEs) and renal-related TEAEs in the core study were not increased with prolonged Lesinurad exposure in the extension study. Patients receiving Lesinurad plus febuxostat therapy for 2 years continued to be at sUA target. Patients exhibited a progressive increase in CR of at least one target tophus, progressive reduction in tophus size, and reduction of gout flares requiring treatment over the second year, with AEs consistent with those observed in the core study. ClinicalTrials.gov , NCT01510769 . Registered on 13 January 2012.

  • Additional file 1: of Efficacy and safety during extended treatment of Lesinurad in combination with febuxostat in patients with tophaceous gout: CRYSTAL extension study
    2019
    Co-Authors: Nicola Dalbeth, Maple Fung, Robert Terkeltaub, Scott Baumgartner, Graeme Jones, Dinesh Khanna, Fernando Perez-ruiz
    Abstract:

    Table S1. Renal-related and kidney stone TEAEs. Table S2. TEAEs with > 5% of patients in either total treatment group during the extension study (safety population). CONT Continuation of Lesinurad treatment, CROSS Crossover from core study placebo to Lesinurad treatment. Figure S1. Patient disposition. *Subjects terminated any time during the study. (DOCX 88 kb

  • Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor a 6 month phase 3 clinical trial and extension study
    Rheumatology, 2017
    Co-Authors: Anne-kathrin Tausche, C. Storgard, Maple Fung, Nicola Dalbeth, R Alten, J Kopicko, Scott Adler, N Bhakta, Scott Baumgartner, Kenneth G Saag
    Abstract:

    Objective: To investigate the efficacy and safety of Lesinurad, a selective uric acid reabsorption inhibitor, in a 6 month, phase 3 clinical trial and extension study. Methods: Patients with gout who cannot take a xanthine oxidase inhibitor (XOI) and have serum uric acid (sUA) ⩾6.5 mg/dl were randomized to receive oral Lesinurad (400 mg daily) or placebo. The primary endpoint was the proportion of patients with sUA <6.0 mg/dl at month 6. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory data. Patients who completed the study were eligible for an open-label, uncontrolled extension study of Lesinurad 400 mg monotherapy. Results: Patients (n = 214) were primarily white males (mean age 54.4 years; gout duration 11.2 years). Significantly more patients achieved the primary endpoint with Lesinurad than placebo (29.9 vs 1.9%; P < 0.0001). Overall TEAE rates were higher with Lesinurad (77.6 vs 65.4%); renal-related TEAEs (17.8%), renal-related serious TEAEs (4.7%) and serum creatinine elevations (1.5 times baseline, 24.3%) occurred only with Lesinurad. A total of 143 patients (65 Lesinurad, 78 placebo) enrolled in the extension study. Treatment with Lesinurad 400 mg resulted in rapid and sustained sUA lowering that persisted for up to 18 months before the study was terminated prematurely. No new safety findings were observed in the extension. Conclusion: In patients with gout and intolerance/contraindication to XOIs, Lesinurad 400 mg monotherapy demonstrated superior sUA lowering compared with placebo, with sustained effects for up to 18 months. Due to a high incidence of serum creatinine elevations and renal-related adverse events, including serious adverse events with Lesinurad 400 mg, Lesinurad should not be used as monotherapy. Trial registration: ClinicalTrials.gov (http://clinincaltrials.gov), NCT01508702.

  • Lesinurad a selective uric acid reabsorption inhibitor in combination with febuxostat in patients with tophaceous gout findings of a phase iii clinical trial
    Arthritis & Rheumatism, 2017
    Co-Authors: Nicola Dalbeth, C. Storgard, Maple Fung, Robert Terkeltaub, J Kopicko, Scott Adler, Graeme Jones, Dinesh Khanna, Nihar Bhakta, Scott Baumgartner
    Abstract:

    Author(s): Dalbeth, Nicola; Jones, Graeme; Terkeltaub, Robert; Khanna, Dinesh; Kopicko, Jeff; Bhakta, Nihar; Adler, Scott; Fung, Maple; Storgard, Chris; Baumgartner, Scott; Perez-Ruiz, Fernando | Abstract: To investigate the efficacy and safety of Lesinurad in combination with febuxostat in a 12-month phase III trial in patients with tophaceous gout.Patients with serum urate (UA) ≥8.0 mg/dl (≥6.0 mg/dl with urate-lowering therapy) and ≥1 measurable target tophus were given febuxostat 80 mg/day for 3 weeks before randomization to receive Lesinurad (200 or 400 mg daily) or placebo in addition to the febuxostat. The primary end point was the proportion of patients achieving a serum UA level of l5.0 mg/dl (month 6). The key secondary end point was the proportion of patients with complete resolution of ≥1 target tophus (month 12). Other end points included the percentage change in total target tophi area. Safety assessments included adverse events and laboratory data.Patients (n = 324) were predominantly male, with a mean age of 54.1 years. Significantly more patients achieved the serum UA target by month 6 with the addition of Lesinurad 400 mg (76.1%; P l 0.0001), but not 200 mg (56.6%; P = 0.13), to the febuxostat therapy as compared with febuxostat alone (46.8%). At all other time points, significantly more patients in the Lesinurad 200 mg group achieved the serum UA target. The number of patients with complete tophus resolution was not different between groups. Treatment with Lesinurad (200 mg and 400 mg) plus febuxostat reduced the total target tophi area as compared with febuxostat alone (50.1% and 52.9% versus 28.3%, respectively; P l 0.05). Safety was generally comparable with that of febuxostat alone, except for higher rates of predominantly reversible elevations in the serum creatinine level, particularly with Lesinurad 400 mg.Treatment with Lesinurad in combination with febuxostat demonstrated superior lowering of serum UA levels as compared with febuxostat alone, with clinically relevant added effects on tophi and an acceptable safety profile with Lesinurad 200 mg in patients with tophaceous gout warranting additional therapy.

  • 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
    Annals of the Rheumatic Diseases, 2017
    Co-Authors: Thomas Bardin, C. Storgard, Maple Fung, J Kopicko, Scott Adler, N Bhakta, Scott Baumgartner, Robert T Keenan, Puja P Khanna, Alexander So
    Abstract:

    Objectives Determine the efficacy and safety of daily Lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial. Methods Patients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of Results Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p Conclusion Lesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and Lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy. Trial registration number NCT01493531.