Febuxostat

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

  • efficacy and safety of Febuxostat extended and immediate release in patients with gout and renal impairment a phase iii placebo controlled study
    Arthritis & Rheumatism, 2019
    Co-Authors: Kenneth G. Saag, Andrew Whelton, Barbara Hunt, Majin Castillo, Michael Becker, K Kisfalvi, Lhanoo Gunawardhana
    Abstract:

    OBJECTIVE To assess the efficacy and safety of Febuxostat extended release (XR) and immediate release (IR) in patients with gout and normal or impaired renal function. METHODS This was a 3-month, phase III, multicenter, double-blind, placebo-controlled study. Patients (n = 1,790) with a history of gout and normal or impaired (mild-to-severe) renal function were randomized to receive placebo, Febuxostat IR 40 or 80 mg, or Febuxostat XR 40 or 80 mg once daily (1:1:1:1:1 ratio). End points included proportions of patients with a serum urate (UA) level of <5.0 mg/dl at month 3 (primary end point), a serum UA level of <6.0 mg/dl at month 3, and ≥1 gout flare requiring treatment over 3 months (secondary end points). RESULTS Both Febuxostat formulations led to significantly greater proportions of patients achieving a serum UA level of <5.0 mg/dl or <6.0 mg/dl at month 3 (P < 0.001 for all comparisons versus placebo). Equivalent doses of Febuxostat XR and IR had similar treatment effects on serum UA level end points; however, a significantly greater proportion of patients achieved a serum UA level of <5.0 mg/dl with XR 40 mg versus IR 40 mg. Similar proportions of patients experienced ≥1 gout flare across treatment groups. Rates of treatment-emergent adverse events were low and evenly distributed between treatment arms. A preplanned subgroup analysis demonstrated that Febuxostat formulations were well tolerated and generally effective on serum UA level end points (versus placebo) across all renal function subgroups. CONCLUSION Both formulations of Febuxostat (XR and IR) were well tolerated and effective in patients with gout and normal or impaired renal function, including patients with severe renal impairment.

  • impact of Febuxostat on renal function in gout patients with moderate to severe renal impairment
    Arthritis & Rheumatism, 2016
    Co-Authors: Kenneth G. Saag, Andrew Whelton, Barbara Hunt, Michael Becker, Patricia A. Macdonald, Lhanoo Gunawardhana
    Abstract:

    Objective Renal impairment is a risk factor for gout and a barrier to optimal gout management. We undertook this exploratory study to obtain data that have been heretofore limited regarding the safety and efficacy of Febuxostat in patients with moderate-to-severe renal impairment (estimated glomerular filtration rate [GFR] 15–50 ml/minute/1.73 m2). Methods Ninety-six gout patients with moderate-to-severe renal impairment were enrolled in a 12-month multicenter, randomized, double-blind, placebo-controlled study. Patients were randomly assigned at a 1:1:1 ratio to receive 30 mg Febuxostat twice daily, 40/80 mg Febuxostat once daily, or placebo. The primary efficacy end point was the change in serum creatinine (Cr) level from baseline to month 12. Secondary end points included the change in estimated GFR from baseline to month 12 and the proportion of patients with a serum uric acid (UA) level of <6.0 mg/dl at month 12. Results At month 12, there were no significant differences in the change in serum Cr level from baseline, or in the change in estimated GFR from baseline, in either Febuxostat group compared to the placebo group. The proportion of patients with a serum UA level of <6.0 mg/dl at month 12 was significantly greater in both Febuxostat groups compared to the placebo group (both P < 0.001). At least 1 treatment-emergent adverse event (TEAE) occurred in 78.1% of patients receiving 30 mg Febuxostat twice daily, 87.5% of patients receiving 40/80 mg Febuxostat once daily, and 78.1% of patients receiving placebo. TEAEs most frequently involved the categories of renal failure and impairment and renal function analyses. Conclusion Febuxostat proved to be efficacious in serum UA reduction and was well tolerated in gout patients with moderate-to-severe renal impairment. Patients randomly assigned to receive Febuxostat demonstrated significantly lower serum UA levels and no significant deterioration in renal function.

  • the urate lowering efficacy and safety of Febuxostat in the treatment of the hyperuricemia of gout the confirms trial
    Arthritis Research & Therapy, 2010
    Co-Authors: Michael Becker, Patricia A. Macdonald, Ralph H Schumacher, Luis R Espinoza, Alvin F Wells, Eric E Lloyd, Christopher Lademacher
    Abstract:

    The purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily Febuxostat and allopurinol in subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial. Subjects (n = 2,269) were randomized to Febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death. Comorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); and hypertension (53%). In Febuxostat 40 mg, Febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but Febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with Febuxostat 80 mg (72%; P < 0.001) compared with Febuxostat 40 mg (50%) or allopurinol (42%), but Febuxostat 40 mg showed greater efficacy than allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for Febuxostat 40 mg and 0.4% for both Febuxostat 80 mg and allopurinol. One death occurred in each Febuxostat group and three in the allopurinol group. Urate-lowering efficacy of Febuxostat 80 mg exceeded that of Febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both Febuxostat doses were more efficacious than allopurinol and equally safe. At the doses tested, safety of Febuxostat and allopurinol was comparable. NCT00430248

  • clinical efficacy and safety of successful longterm urate lowering with Febuxostat or allopurinol in subjects with gout
    The Journal of Rheumatology, 2009
    Co-Authors: Michael Becker, Patricia A. Macdonald, Ralph H Schumacher, Eric E Lloyd, Christopher Lademacher
    Abstract:

    Objective. To determine longterm urate-lowering efficacy and clinical benefits and safety of therapy with Febuxostat or allopurinol in subjects with gout. Methods. Subjects (n = 1086) in this open-label extension study were assigned to fixed-dose daily urate-lowering treatment (ULT) with Febuxostat (80 mg or 120 mg) or allopurinol (300 mg). ULT reassignment was permitted during months 1 to 6 to achieve serum urate (SUA) concentrations between 3.0 and Results. After 1 month initial treatment, > 80% of subjects receiving either Febuxostat dose, but only 46% of subjects receiving allopurinol, achieved SUA 80% of all remaining subjects maintained the primary efficacy endpoint of SUA Conclusion. Durable maintenance of goal range SUA level with either dose of Febuxostat or in smaller numbers of subjects with allopurinol resulted in near elimination of gout flares and improved tophus status over time. Registered as NCT00175019.

  • effects of Febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout a 28 week phase iii randomized double blind parallel group trial
    Arthritis & Rheumatism, 2008
    Co-Authors: Ralph H Schumacher, Barbara Hunt, Michael Becker, Patricia A. Macdonald, Christopher Lademacher, Robert L Wortmann, Janet Streit, Nancy Josephridge
    Abstract:

    Objective To compare the urate-lowering efficacy and safety of Febuxostat, allopurinol, and placebo in a large group of subjects with hyperuricemia and gout, including persons with impaired renal function. Methods Subjects (n = 1,072) with hyperuricemia (serum urate level ≥8.0 mg/dl) and gout with normal or impaired (serum creatinine level >1.5 to ≤2.0 mg/dl) renal function were randomized to receive once-daily Febuxostat (80 mg, 120 mg, or 240 mg), allopurinol (300 or 100 mg, based on renal function), or placebo for 28 weeks. Results Significantly (P ≤ 0.05) higher percentages of subjects treated with Febuxostat 80 mg (48%), 120 mg (65%), and 240 mg (69%) attained the primary end point of last 3 monthly serum urate levels <6.0 mg/dl compared with allopurinol (22%) and placebo (0%). A significantly (P < 0.05) higher percentage of subjects with impaired renal function treated with Febuxostat 80 mg (4 [44%] of 9), 120 mg (5 [45%] of 11), and 240 mg (3 [60%] of 5) achieved the primary end point compared with those treated with 100 mg of allopurinol (0 [0%] of 10). Proportions of subjects experiencing any adverse event or serious adverse event were similar across groups, although diarrhea and dizziness were more frequent in the Febuxostat 240 mg group. The primary reasons for withdrawal were similar across groups except for gout flares, which were more frequent with Febuxostat than with allopurinol. Conclusion At all doses studied, Febuxostat more effectively lowered and maintained serum urate levels <6.0 mg/dl than did allopurinol (300 or 100 mg) or placebo in subjects with hyperuricemia and gout, including those with mild to moderately impaired renal function.

Nancy Josephridge - One of the best experts on this subject based on the ideXlab platform.

  • effects of Febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout a 28 week phase iii randomized double blind parallel group trial
    Arthritis & Rheumatism, 2008
    Co-Authors: Ralph H Schumacher, Barbara Hunt, Michael Becker, Patricia A. Macdonald, Christopher Lademacher, Robert L Wortmann, Janet Streit, Nancy Josephridge
    Abstract:

    Objective To compare the urate-lowering efficacy and safety of Febuxostat, allopurinol, and placebo in a large group of subjects with hyperuricemia and gout, including persons with impaired renal function. Methods Subjects (n = 1,072) with hyperuricemia (serum urate level ≥8.0 mg/dl) and gout with normal or impaired (serum creatinine level >1.5 to ≤2.0 mg/dl) renal function were randomized to receive once-daily Febuxostat (80 mg, 120 mg, or 240 mg), allopurinol (300 or 100 mg, based on renal function), or placebo for 28 weeks. Results Significantly (P ≤ 0.05) higher percentages of subjects treated with Febuxostat 80 mg (48%), 120 mg (65%), and 240 mg (69%) attained the primary end point of last 3 monthly serum urate levels <6.0 mg/dl compared with allopurinol (22%) and placebo (0%). A significantly (P < 0.05) higher percentage of subjects with impaired renal function treated with Febuxostat 80 mg (4 [44%] of 9), 120 mg (5 [45%] of 11), and 240 mg (3 [60%] of 5) achieved the primary end point compared with those treated with 100 mg of allopurinol (0 [0%] of 10). Proportions of subjects experiencing any adverse event or serious adverse event were similar across groups, although diarrhea and dizziness were more frequent in the Febuxostat 240 mg group. The primary reasons for withdrawal were similar across groups except for gout flares, which were more frequent with Febuxostat than with allopurinol. Conclusion At all doses studied, Febuxostat more effectively lowered and maintained serum urate levels <6.0 mg/dl than did allopurinol (300 or 100 mg) or placebo in subjects with hyperuricemia and gout, including those with mild to moderately impaired renal function.

  • the effect of age and gender on pharmacokinetics pharmacodynamics and safety of Febuxostat a novel nonpurine selective inhibitor of xanthine oxidase
    The Journal of Clinical Pharmacology, 2008
    Co-Authors: Reza Khosravan, Nancy Josephridge, Laurent Vernillet, Michael J Kukulka
    Abstract:

    Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase, which is currently being developed for the management of hyperuricemia in patients with gout. The effect of age and gender on the pharmacokinetics, pharmacodynamics, and safety of once-daily oral Febuxostat 80 mg was assessed in healthy male and female subjects after 7 days. Following multiple dosing with Febuxostat, there were no statistically significant differences in the plasma or urinary pharmacokinetic or pharmacodynamic parameters between subjects aged 18 to 40 years and >or=65 years. Although unbound peak concentration (C(max,u)) and area under the concentration-time curve (AUC(24,u)) for Febuxostat were higher in women as compared with men (31.5 vs 23.6 ng/mL, P uric acid 24-hour mean concentration was slightly greater in women than in men (59% vs 52%, P Febuxostat was well tolerated in male and female subjects in both age groups. Age or gender had no clinically significant effect on the pharmacokinetics, pharmacodynamics, or safety of Febuxostat. Therefore, Febuxostat does not require any dose adjustments based on age or gender.

  • pharmacokinetic interactions of concomitant administration of Febuxostat and nsaids
    The Journal of Clinical Pharmacology, 2006
    Co-Authors: Reza Khosravan, Nancy Josephridge, Laurent Vernillet
    Abstract:

    To evaluate the effect of Febuxostat on the pharmacokinetics of indomethacin and naproxen and vice versa, 2 multiple-dose, 3-period crossover studies were performed in healthy subjects. In study 1, subjects received Febuxostat 80 mg once daily, indomethacin 50 mg twice daily, or both. In study 2, subjects received Febuxostat 80 mg, naproxen 500 mg twice daily, or both. Twenty-four-hour blood samples were collected on day 5 in study 1 and day 7 in study 2. In study 1, 90% confidence intervals of geometric mean ratios for maximum plasma concentration (Cmax) and area under the curve (AUC) were within the 0.80 to 1.25 no-effect range for Febuxostat and indomethacin. In study 2, 90% confidence intervals for Febuxostat C(max) and AUC extended above that range, with increases of 28% and 40% in Cmax and AUC24, respectively. However, 90% confidence intervals for naproxen C(max) and AUC were within the 0.80 to 1.25 range. Febuxostat had no effect on the plasma pharmacokinetics of indomethacin and naproxen. Similarly, indomethacin had no effect on the plasma pharmacokinetics of Febuxostat. Although naproxen caused an increase in plasma exposure to Febuxostat, this increase is not expected to be clinically significant. Therefore, based on the plasma pharmacokinetic data in healthy subjects, Febuxostat may be administered with indomethacin or naproxen with no dose adjustments for Febuxostat, indomethacin, or naproxen.

  • the effect of mild and moderate hepatic impairment on pharmacokinetics pharmacodynamics and safety of Febuxostat a novel nonpurine selective inhibitor of xanthine oxidase
    The Journal of Clinical Pharmacology, 2006
    Co-Authors: Reza Khosravan, Brian A Grabowski, Michael D Mayer, Jingtao Wu, Nancy Josephridge, Laurent Vernillet
    Abstract:

    To assess the effect of hepatic impairment on the pharmacokinetics, pharmacodynamics, and safety of Febuxostat at steady state, multiple once-daily 80-mg oral doses of Febuxostat were administered to subjects with normal hepatic function and to subjects with mild or moderate hepatic impairment. There were no statistically significant differences in the plasma pharmacokinetic parameters for unbound Febuxostat and its active metabolites between subjects with mild or moderate hepatic impairment and those with normal hepatic function. The percentage decrease in serum uric acid appeared to be lower in hepatic impairment groups (49% [mild] and 48% [moderate]) as compared to the normal hepatic group (62%). This lower percentage decrease was minimal and not considered clinically significant. Febuxostat 80 mg once daily appears to be generally safe and well tolerated in mildly and moderately impaired hepatic function groups, and dose adjustment is not required in subjects with mild to moderate hepatic impairment.

  • Febuxostat compared with allopurinol in patients with hyperuricemia and gout
    The New England Journal of Medicine, 2005
    Co-Authors: Michael Becker, Patricia A. Macdonald, Ralph H Schumacher, Robert L Wortmann, Denise Eustace, William A Palo, Janet Streit, Nancy Josephridge
    Abstract:

    background Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout. methods We randomly assigned 762 patients with gout and with serum urate concentrations of at least 8.0 mg per deciliter (480 µmol per liter) to receive either Febuxostat (80 mg or 120 mg) or allopurinol (300 mg) once daily for 52 weeks; 760 received the study drug. Prophylaxis against gout flares with naproxen or colchicine was provided during weeks 1 through 8. The primary end point was a serum urate concentration of less than 6.0 mg per deciliter (360 µmol per liter) at the last three monthly measurements. The secondary end points included reduction in the incidence of gout flares and in tophus area. results The primary end point was reached in 53 percent of patients receiving 80 mg of Febuxostat, 62 percent of those receiving 120 mg of Febuxostat, and 21 percent of those receiving allopurinol (P<0.001 for the comparison of each Febuxostat group with the allopurinol group). Although the incidence of gout flares diminished with continued treatment, the overall incidence during weeks 9 through 52 was similar in all groups: 64 percent of patients receiving 80 mg of Febuxostat, 70 percent of those receiving 120 mg of Febuxostat, and 64 percent of those receiving allopurinol (P=0.99 for 80 mg of Febuxostat vs. allopurinol; P = 0.23 for 120 mg of Febuxostat vs. allopurinol). The median reduction in tophus area was 83 percent in patients receiving 80 mg of Febuxostat and 66 percent in those receiving 120 mg of Febuxostat, as compared with 50 percent in those receiving allopurinol (P=0.08 for 80 mg of Febuxostat vs. allopurinol; P=0.16 for 120 mg of Febuxostat vs. allopurinol). More patients in the high-dose Febuxostat group than in the allopurinol group (P=0.003) or the low-dose Febuxostat group discontinued the study. Four of the 507 patients in the two Febuxostat groups (0.8 percent) and none of the 253 patients in the allopurinol group died; all deaths were from causes that the investigators (while still blinded to treatment) judged to be unrelated to the study drugs (P=0.31 for the comparison between the combined Febuxostat groups and the allopurinol group). conclusions Febuxostat, at a daily dose of 80 mg or 120 mg, was more effective than allopurinol at the commonly used fixed daily dose of 300 mg in lowering serum urate. Similar reductions in gout flares and tophus area occurred in all treatment groups.

Ralph H Schumacher - One of the best experts on this subject based on the ideXlab platform.

  • Clinical Efficacy and Safety of Successful Longterm Urate Lowering with Febuxostat or Allopurinol in Subjects with Gout
    2020
    Co-Authors: Michael A. Becker, Patricia A. Macdonald, Ralph H Schumacher, Eric Lloyd, Christopher Lademacher
    Abstract:

    ABSTRACT. Objective. To determine longterm urate-lowering efficacy and clinical benefits and safety of therapy with Febuxostat or allopurinol in subjects with gout. Methods. Subjects (n = 1086) in this open-label extension study were assigned to fixed-dose daily urate-lowering treatment (ULT) with Febuxostat (80 mg or 120 mg) or allopurinol (300 mg). ULT reassignment was permitted during months 1 to 6 to achieve serum urate (SUA) concentrations between 3.0 and < 6.0 mg/dl. Flares requiring treatment, tophus size, safety, and SUA levels were monitored during up to 40 months of ULT maintenance. Results. After 1 month initial treatment, > 80% of subjects receiving either Febuxostat dose, but only 46% of subjects receiving allopurinol, achieved SUA < 6.0 mg/dl. After ULT reassignment, > 80% of all remaining subjects maintained the primary efficacy endpoint of SUA < 6.0 mg/dl at each visit. More subjects initially randomized to allopurinol required ULT reassignment to achieve SUA < 6.0 mg/dl compared with subjects receiving Febuxostat. Maintenance of SUA < 6.0 mg/dl resulted in progressive reduction to nearly 0 in proportion of subjects requiring gout flare treatment. Baseline tophus resolution was achieved by 46%, 36%, and 29% of subjects maintained on Febuxostat 80 mg, Febuxostat 120 mg, and allopurinol, respectively. Overall adverse event rates (including cardiovascular adverse event rates), adjusted for 10-fold greater Febuxostat than allopurinol exposure, did not differ significantly among treatment groups. Conclusion. Durable maintenance of goal range SUA level with either dose of Febuxostat or in smaller numbers of subjects with allopurinol resulted in near elimination of gout flares and improved tophus status over time

  • Personal non-commercial use only. The Journal of Rheumatology Registered as NCT00175019. (First Release
    2020
    Co-Authors: Michael A. Becker, Patricia A. Macdonald, Ralph H Schumacher, Eric Lloyd, Christopher Lademacher
    Abstract:

    ABSTRACT. Objective. To determine longterm urate-lowering efficacy and clinical benefits and safety of therapy with Febuxostat or allopurinol in subjects with gout. Methods. Subjects (n = 1086) in this open-label extension study were assigned to fixed-dose daily urate-lowering treatment (ULT) with Febuxostat (80 mg or 120 mg) or allopurinol (300 mg). ULT reassignment was permitted during months 1 to 6 to achieve serum urate (SUA) concentrations between 3.0 and < 6.0 mg/dl. Flares requiring treatment, tophus size, safety, and SUA levels were monitored during up to 40 months of ULT maintenance. Results. After 1 month initial treatment, > 80% of subjects receiving either Febuxostat dose, but only 46% of subjects receiving allopurinol, achieved SUA < 6.0 mg/dl. After ULT reassignment, > 80% of all remaining subjects maintained the primary efficacy endpoint of SUA < 6.0 mg/dl at each visit. More subjects initially randomized to allopurinol required ULT reassignment to achieve SUA < 6.0 mg/dl compared with subjects receiving Febuxostat. Maintenance of SUA < 6.0 mg/dl resulted in progressive reduction to nearly 0 in proportion of subjects requiring gout flare treatment. Baseline tophus resolution was achieved by 46%, 36%, and 29% of subjects maintained on Febuxostat 80 mg, Febuxostat 120 mg, and allopurinol, respectively. Overall adverse event rates (including cardiovascular adverse event rates), adjusted for 10-fold greater Febuxostat than allopurinol exposure, did not differ significantly among treatment groups. Conclusion. Durable maintenance of goal range SUA level with either dose of Febuxostat or in smaller numbers of subjects with allopurinol resulted in near elimination of gout flares and improved tophus status over time

  • the urate lowering efficacy and safety of Febuxostat in the treatment of the hyperuricemia of gout the confirms trial
    Arthritis Research & Therapy, 2010
    Co-Authors: Michael Becker, Patricia A. Macdonald, Ralph H Schumacher, Luis R Espinoza, Alvin F Wells, Eric E Lloyd, Christopher Lademacher
    Abstract:

    The purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily Febuxostat and allopurinol in subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial. Subjects (n = 2,269) were randomized to Febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death. Comorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); and hypertension (53%). In Febuxostat 40 mg, Febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but Febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with Febuxostat 80 mg (72%; P < 0.001) compared with Febuxostat 40 mg (50%) or allopurinol (42%), but Febuxostat 40 mg showed greater efficacy than allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for Febuxostat 40 mg and 0.4% for both Febuxostat 80 mg and allopurinol. One death occurred in each Febuxostat group and three in the allopurinol group. Urate-lowering efficacy of Febuxostat 80 mg exceeded that of Febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both Febuxostat doses were more efficacious than allopurinol and equally safe. At the doses tested, safety of Febuxostat and allopurinol was comparable. NCT00430248

  • clinical efficacy and safety of successful longterm urate lowering with Febuxostat or allopurinol in subjects with gout
    The Journal of Rheumatology, 2009
    Co-Authors: Michael Becker, Patricia A. Macdonald, Ralph H Schumacher, Eric E Lloyd, Christopher Lademacher
    Abstract:

    Objective. To determine longterm urate-lowering efficacy and clinical benefits and safety of therapy with Febuxostat or allopurinol in subjects with gout. Methods. Subjects (n = 1086) in this open-label extension study were assigned to fixed-dose daily urate-lowering treatment (ULT) with Febuxostat (80 mg or 120 mg) or allopurinol (300 mg). ULT reassignment was permitted during months 1 to 6 to achieve serum urate (SUA) concentrations between 3.0 and Results. After 1 month initial treatment, > 80% of subjects receiving either Febuxostat dose, but only 46% of subjects receiving allopurinol, achieved SUA 80% of all remaining subjects maintained the primary efficacy endpoint of SUA Conclusion. Durable maintenance of goal range SUA level with either dose of Febuxostat or in smaller numbers of subjects with allopurinol resulted in near elimination of gout flares and improved tophus status over time. Registered as NCT00175019.

  • effects of Febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout a 28 week phase iii randomized double blind parallel group trial
    Arthritis & Rheumatism, 2008
    Co-Authors: Ralph H Schumacher, Barbara Hunt, Michael Becker, Patricia A. Macdonald, Christopher Lademacher, Robert L Wortmann, Janet Streit, Nancy Josephridge
    Abstract:

    Objective To compare the urate-lowering efficacy and safety of Febuxostat, allopurinol, and placebo in a large group of subjects with hyperuricemia and gout, including persons with impaired renal function. Methods Subjects (n = 1,072) with hyperuricemia (serum urate level ≥8.0 mg/dl) and gout with normal or impaired (serum creatinine level >1.5 to ≤2.0 mg/dl) renal function were randomized to receive once-daily Febuxostat (80 mg, 120 mg, or 240 mg), allopurinol (300 or 100 mg, based on renal function), or placebo for 28 weeks. Results Significantly (P ≤ 0.05) higher percentages of subjects treated with Febuxostat 80 mg (48%), 120 mg (65%), and 240 mg (69%) attained the primary end point of last 3 monthly serum urate levels <6.0 mg/dl compared with allopurinol (22%) and placebo (0%). A significantly (P < 0.05) higher percentage of subjects with impaired renal function treated with Febuxostat 80 mg (4 [44%] of 9), 120 mg (5 [45%] of 11), and 240 mg (3 [60%] of 5) achieved the primary end point compared with those treated with 100 mg of allopurinol (0 [0%] of 10). Proportions of subjects experiencing any adverse event or serious adverse event were similar across groups, although diarrhea and dizziness were more frequent in the Febuxostat 240 mg group. The primary reasons for withdrawal were similar across groups except for gout flares, which were more frequent with Febuxostat than with allopurinol. Conclusion At all doses studied, Febuxostat more effectively lowered and maintained serum urate levels <6.0 mg/dl than did allopurinol (300 or 100 mg) or placebo in subjects with hyperuricemia and gout, including those with mild to moderately impaired renal function.

Robert Terkeltaub - One of the best experts on this subject based on the ideXlab platform.

  • effect of intensive urate lowering with combined verinurad and Febuxostat on albuminuria in patients with type 2 diabetes a randomized trial
    American Journal of Kidney Diseases, 2021
    Co-Authors: Austin G Stack, Nalina Dronamraju, Joanna Parkinson, Susanne Johansson, E Johnsson, Fredrik Erlandsson, Robert Terkeltaub
    Abstract:

    Rationale & Objective Hyperuricemia has been implicated in the development and progression of chronic kidney disease. Verinurad is a novel, potent, specific urate reabsorption inhibitor. We evaluated the effects on albuminuria of intensive urate-lowering therapy with verinurad combined with the xanthine oxidase inhibitor Febuxostat in patients with hyperuricemia and type 2 diabetes mellitus (T2DM). Study Design Phase 2, multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial. Setting & Participants Patients 18 years or older with hyperuricemia, albuminuria, and T2DM. Intervention Patients randomly assigned 1:1 to verinurad (9mg) plus Febuxostat (80mg) or matched placebo once daily for 24 weeks. Outcomes The primary end point was change in urinary albumin-creatinine ratio (UACR) from baseline after 12 weeks' treatment. Secondary end points included safety and tolerability and effect on glomerular filtration. Results 60 patients were enrolled (n=32, verinurad and Febuxostat; n=28, placebo). UACRs after treatment with verinurad plus Febuxostat were lower than after placebo at 1, 12, and 24 weeks: −38.6% (90% CI, −60.9% to−3.6%), −39.4% (90% CI, −61.8% to−3.8%), and−49.3% (90% CI, −68.2% to−19.0%), respectively. Serum urate levels after treatment with verinurad plus Febuxostat were 59.6% and 63.7% lower than after placebo at 12 and 24 weeks, respectively. No clinically meaningful changes were observed in estimated glomerular filtration rate or serum creatinine or serum cystatin C concentrations. Verinurad plus Febuxostat was well tolerated. Limitations Sample size and study duration were insufficient to evaluate definitive effects of verinurad plus Febuxostat on UACR and glomerular filtration. Generalizability was limited by exclusion of patients with stages 4 and 5 chronic kidney disease. Conclusions Verinurad plus Febuxostat reduced albuminuria and lowered serum urate concentrations in patients with T2DM, albuminuria, and hyperuricemia. Definitive assessment of their combined impact on preservation of kidney function awaits larger clinical studies. Funding This study was supported by AstraZeneca. Trial Registration Registered at ClinicalTrials.gov with study number NCT03118739.

  • reassessing the cardiovascular safety of Febuxostat implications of the fast study
    Arthritis & Rheumatism, 2021
    Co-Authors: Hyon K Choi, Tuhina Neogi, Lisa K Stamp, Robert Terkeltaub, Nicola Dalbeth
    Abstract:

    The US FDA-mandated CARES trial, published in 2018, reported increased all-cause and cardiovascular (CV) death in participants randomized to Febuxostat compared with allopurinol. The subsequent FDA Drug Safety Communication and Boxed Warning resulted in substantial reductions in Febuxostat use in the US. The EMA-mandated Febuxostat versus Allopurinol Streamlined Trial (FAST), published in 2020, found no increased risk of composite CV events, CV mortality or all-cause mortality for Febuxostat, compared with allopurinol. This commentary discusses implications of these new findings for gout management.

  • new perspectives in rheumatology implications of the cardiovascular safety of Febuxostat and allopurinol in patients with gout and cardiovascular morbidities trial and the associated food and drug administration public safety alert
    Arthritis & Rheumatism, 2018
    Co-Authors: Hyon K Choi, Tuhina Neogi, Lisa K Stamp, Nicola Dalbeth, Robert Terkeltaub
    Abstract:

    Recently, the US Food and Drug Administration (FDA) issued a public safety alert, responding to the results of the now-published Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities (CARES) trial. The CARES trial showed no significant difference between allopurinol and Febuxostat in the primary composite end point of cardiovascular (CV) events in subjects with gout and established CV comorbidities at baseline. However, there was a significantly increased risk of CV and all-cause mortality with Febuxostat. Urate-lowering therapy (ULT) is central to the long-term management of gout, and xanthine oxidoreductase inhibitor (XOI) therapy is the consensus first-line approach. Allopurinol is generally the first XOI used, but Febuxostat is an effective XOI option, and is commonly used when allopurinol is not tolerated. These data are further relevant since CV comorbidities are common in gout. Here, we examine why the CARES trial was done, and discuss other, ongoing comparative studies of Febuxostat and allopurinol whose results are awaited. We assess the strengths and limitations of the CARES trial, and appraise the robustness and biologic plausibility of the results. The CARES trial does not prove that Febuxostat raises CV mortality risk, but suggests greater risk with Febuxostat than allopurinol. The CARES trial results do not support first-line use of Febuxostat ULT, and raise questions about Febuxostat placement at various pharmacologic ULT decision tree branches. Alternatives to Febuxostat that are frequently effective include allopurinol dose escalation and uricosuric therapy alone or combined with allopurinol. The FDA safety alert highlights the need for shared ULT medical decision-making with gout patients, including discussion of the CV safety of Febuxostat.

  • 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, 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 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, Scott Adler, Graeme Jones, Dinesh Khanna, Nihar Bhakta, J Kopicko, 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: ObjectiveTo investigate the efficacy and safety of lesinurad in combination with Febuxostat in a 12-month phase III trial in patients with tophaceous gout.MethodsPatients 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.ResultsPatients (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.ConclusionTreatment 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.

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  • metabolism and excretion of 14c Febuxostat a novel nonpurine selective inhibitor of xanthine oxidase in healthy male subjects
    The Journal of Clinical Pharmacology, 2011
    Co-Authors: Brian Grabowski, Reza Khosravan, Laurent Vernillet, Darcy Mulford
    Abstract:

    Absorption, metabolism, and excretion of one 80 mg oral dose of [(14)C] Febuxostat ([thiazole-4-(14)C] 2-[3-cyano-4-isobutoxyphenyl]-4-methyl-5-thiazolecarboxylic acid) were studied in 6 healthy subjects. Mean cumulative recovery in excreta was 94% (49% urine and 45% feces) of the dose over 9 days; 87% of the dose was profiled. Seventeen radioactive peaks were observed in urine and fecal chromatograms. Unchanged Febuxostat contributed to a combined total in excreta of 10% to 18% of the dose, indicating that it was extensively metabolized and well absorbed. Metabolites were 67M-1 (10%) and 67M-2 (11%) hydroxylated Febuxostat, Febuxostat acyl-glucuronide (30%), 67M-4 di-carboxylic acid (14%), 67M-1 sulfate conjugate (3%), and dehydrated 67M-1/67M-2 acyl-glucuronide (0.5%). Febuxostat and these metabolites accounted for 82% of profiled dose; unidentified peaks individually contributed <1.3% of the dose. Febuxostat and total radioactivity plasma C(max) values were observed at 0.5 hour postdose, suggesting that Febuxostat was quickly absorbed. At 4 hours postdose, plasma chromatographic profiles contained 6 peaks: Febuxostat (85%), 67M-1 (4%), 67M-2 (5%), Febuxostat acyl-glucuronide (4%), 67M-4 (1%), and 67M-1 sulfate (0.5%). Compared to total radioactivity, Febuxostat accounted for 94% at C(max) and 83% of the area under the concentration-time curve (AUC) values. Based on the whole blood to plasma total radioactivity, little radioactivity was associated with red blood cells.

  • effect of hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of Febuxostat a non purine selective inhibitor of xanthine oxidase
    British Journal of Clinical Pharmacology, 2010
    Co-Authors: Brian Grabowski, Reza Khosravan, Laurent Vernillet, Christopher Lademacher
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Hyperuricaemia and gout frequently coexist with cardiovascular disorders such as hypertension and heart failure. The use of diuretics has been re-established as a first-line treatment for patients with hypertension and the effects of diuretics on serum uric acid may diminish the urate-lowering effects of Febuxostat, a novel, potent, non-purine selective inhibitor of xanthine oxidase. WHAT THIS STUDY ADDS • Co-administration of Febuxostat 80 mg and hydrochlorothiazide 50 mg had no effect on the pharmacokinetics and did not have a clinically significant effect on the pharmacodynamics of Febuxostat. Dose adjustment for Febuxostat is not necessary when it is administered with hydrochlorothiazide. AIM This study examined the effect of co-administration of Febuxostat, an investigational urate lowering therapy, and hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of Febuxostat. METHODS Healthy subjects (36 healthy men and women) received single doses of Febuxostat 80 mg alone and Febuxostat 80 mg + hydrochlorothiazide 50 mg, separated by 7 days in an open-label, randomized, crossover fashion. Plasma concentrations of Febuxostat and urinary and serum concentrations of uric acid were assessed. RESULTS Mean Febuxostat Cmax, AUC(0–t), AUC(0–∞), t1/2,z, CL/F and Vss/F values for regimens co-administration/Febuxostat alone were 2.9/2.9 µg ml−1, 9.3/9.1 µg ml−1 h, 9.6/9.3 µg ml−1 h, 6.5/6.1 h, 8.8/9.3 l h−1 and 45/44 l, respectively. Geometric mean ratios (co-administration : Febuxostat alone) and their 90% confidence intervals for Febuxostat plasma Cmax, AUC(0–t), and AUC(0–∞) were 1.00 (0.86, 1.17), 1.03 (0.98, 1.09), and 1.04 (0.98, 1.10), respectively; all of the 90% CIs were within the no effect range of 0.8 to 1.25. Serum uric acid Cmean,24h, Cmean,48h and CLR for both regimens co-administration/Febuxostat alone were 216/203 µmol l−1, 218/202 µmol l−1 and 9.1/10.1 ml min−1, respectively. Although serum uric acid Cmean,24h and Cmean,48h values were higher and CLR values lower after co-administration compared with dosing of Febuxostat alone, with the differences being statistically significant (P < 0.003), none of the differences (6.5%–9.5%) was considered clinically significant. CONCLUSION Dose adjustment for Febuxostat is not necessary when it is administered with hydrochlorothiazide.

  • the effect of age and gender on pharmacokinetics pharmacodynamics and safety of Febuxostat a novel nonpurine selective inhibitor of xanthine oxidase
    The Journal of Clinical Pharmacology, 2008
    Co-Authors: Reza Khosravan, Nancy Josephridge, Laurent Vernillet, Michael J Kukulka
    Abstract:

    Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase, which is currently being developed for the management of hyperuricemia in patients with gout. The effect of age and gender on the pharmacokinetics, pharmacodynamics, and safety of once-daily oral Febuxostat 80 mg was assessed in healthy male and female subjects after 7 days. Following multiple dosing with Febuxostat, there were no statistically significant differences in the plasma or urinary pharmacokinetic or pharmacodynamic parameters between subjects aged 18 to 40 years and >or=65 years. Although unbound peak concentration (C(max,u)) and area under the concentration-time curve (AUC(24,u)) for Febuxostat were higher in women as compared with men (31.5 vs 23.6 ng/mL, P uric acid 24-hour mean concentration was slightly greater in women than in men (59% vs 52%, P Febuxostat was well tolerated in male and female subjects in both age groups. Age or gender had no clinically significant effect on the pharmacokinetics, pharmacodynamics, or safety of Febuxostat. Therefore, Febuxostat does not require any dose adjustments based on age or gender.

  • pharmacokinetic interactions of concomitant administration of Febuxostat and nsaids
    The Journal of Clinical Pharmacology, 2006
    Co-Authors: Reza Khosravan, Nancy Josephridge, Laurent Vernillet
    Abstract:

    To evaluate the effect of Febuxostat on the pharmacokinetics of indomethacin and naproxen and vice versa, 2 multiple-dose, 3-period crossover studies were performed in healthy subjects. In study 1, subjects received Febuxostat 80 mg once daily, indomethacin 50 mg twice daily, or both. In study 2, subjects received Febuxostat 80 mg, naproxen 500 mg twice daily, or both. Twenty-four-hour blood samples were collected on day 5 in study 1 and day 7 in study 2. In study 1, 90% confidence intervals of geometric mean ratios for maximum plasma concentration (Cmax) and area under the curve (AUC) were within the 0.80 to 1.25 no-effect range for Febuxostat and indomethacin. In study 2, 90% confidence intervals for Febuxostat C(max) and AUC extended above that range, with increases of 28% and 40% in Cmax and AUC24, respectively. However, 90% confidence intervals for naproxen C(max) and AUC were within the 0.80 to 1.25 range. Febuxostat had no effect on the plasma pharmacokinetics of indomethacin and naproxen. Similarly, indomethacin had no effect on the plasma pharmacokinetics of Febuxostat. Although naproxen caused an increase in plasma exposure to Febuxostat, this increase is not expected to be clinically significant. Therefore, based on the plasma pharmacokinetic data in healthy subjects, Febuxostat may be administered with indomethacin or naproxen with no dose adjustments for Febuxostat, indomethacin, or naproxen.

  • the effect of mild and moderate hepatic impairment on pharmacokinetics pharmacodynamics and safety of Febuxostat a novel nonpurine selective inhibitor of xanthine oxidase
    The Journal of Clinical Pharmacology, 2006
    Co-Authors: Reza Khosravan, Brian A Grabowski, Michael D Mayer, Jingtao Wu, Nancy Josephridge, Laurent Vernillet
    Abstract:

    To assess the effect of hepatic impairment on the pharmacokinetics, pharmacodynamics, and safety of Febuxostat at steady state, multiple once-daily 80-mg oral doses of Febuxostat were administered to subjects with normal hepatic function and to subjects with mild or moderate hepatic impairment. There were no statistically significant differences in the plasma pharmacokinetic parameters for unbound Febuxostat and its active metabolites between subjects with mild or moderate hepatic impairment and those with normal hepatic function. The percentage decrease in serum uric acid appeared to be lower in hepatic impairment groups (49% [mild] and 48% [moderate]) as compared to the normal hepatic group (62%). This lower percentage decrease was minimal and not considered clinically significant. Febuxostat 80 mg once daily appears to be generally safe and well tolerated in mildly and moderately impaired hepatic function groups, and dose adjustment is not required in subjects with mild to moderate hepatic impairment.

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