The Impact of Label Changes (Boxed Warning) on Real-World Febuxostat Utilization in Patients with Gout: A Cross-Sectional Drug Utilization Study.

INTRODUCTION: This drug utilization study evaluated the impact of 2019 label changes on real-world febuxostat utilization among patients with gout. We describe the numbers and proportions of patients initiating febuxostat as new users (allopurinol-naïve) or prevalent new users (prior allopurinol use) and data on febuxostat users with established cardiovascular disease (CVD) morbidities before, during, and after the 2019 label changes. METHODS: This descriptive, non-interventional, cross-sectional study used data from two large administrative claims databases in the United States, the IQVIA PharMetrics Plus database and the Optum Research Database (ORD). The study population included patients with gout initiating febuxostat on or after June 1, 2016. Data were collected on febuxostat and allopurinol use, established CVD morbidities, comorbidities of interest, concomitant medications, and patient demographics. RESULTS: In both databases, the total number of febuxostat users and proportion of patients who initiated febuxostat as new users both decreased during the study period. Of 13,848 patients in the PharMetrics Plus cohort, 42.7% were new users of febuxostat and 57.3% were prevalent new users. In the ORD cohort, 40.5% of the 10,198 patients were new users and 59.5% were prevalent new users. The most common established CVD morbidities in the 12 months prior to initiation of febuxostat were diabetes mellitus, ischemic heart disease, and heart failure/cardiomyopathy. CONCLUSIONS: Although the benefit-risk profile for febuxostat is considered favorable for the treatment of hyperuricemia in certain patients with gout, real-world febuxostat utilization decreased during the study period, presumably in response to the label change.

Evaluation of the Relationship Between Serum Urate Levels, Clinical Manifestations of Gout, and Death From Cardiovascular Causes in Patients Receiving Febuxostat or Allopurinol in an Outcomes Trial.

OBJECTIVE: To investigate whether serum urate levels, number of gout flares, and tophi burden are related to death from cardiovascular (CV) causes after treatment with febuxostat or allopurinol in patients with gout from the Cardiovascular Safety of Febuxostat or Allopurinol in Patients With Gout and Cardiovascular Comorbidities (CARES) trial. METHODS: Patients were randomly assigned to receive febuxostat (40 mg or 80 mg once daily, according to serum urate levels at week 2) or allopurinol titrated in 100-mg increments from 200-400 mg or 300-600 mg (with dose determined according to kidney function). Changes from baseline in serum urate level, gout flares, and tophus resolution were key exploratory efficacy parameters in the overall population and in subgroups of patients who died and those who did not die from a CV-related cause. The latter subgroup included patients who died due to non-CV causes and those who did not die due to any cause. RESULTS: Patients received treatment with febuxostat (n = 3,098) or allopurinol (n = 3,092) for a median follow-up period of 32 months (for a maximum of 85 months). In the overall population, mean serum urate levels were lower in those receiving febuxostat compared with those receiving allopurinol at most study visits. There were no associations between serum urate levels and death from CV causes with febuxostat. The number of gout flares requiring treatment was higher within 1 year of treatment with febuxostat compared with allopurinol (mean incidence of gout flares per patient-years of exposure 1.33 versus 1.20), but was comparable thereafter and decreased overall throughout the study period (mean incidence of gout flares per patient-years of exposure 0.35 versus 0.34 after 1 year of treatment; overall mean incidence 0.68 versus 0.63) irrespective of whether the patient died from a CV-related cause. Overall, 20.8% of patients had ≥1 tophus at baseline; tophus resolution rates were similar between treatment groups, with cumulative resolution rates of >50%. CONCLUSION: In the CARES trial, febuxostat and allopurinol (≤600 mg doses) had comparable efficacy in patients with gout and CV disease, and there was no evidence of a relationship between death from CV causes and serum urate levels, number of gout flares, or tophus resolution among the patients receiving febuxostat.

Efficacy and Safety of Lisdexamfetamine in Preschool Children With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: To evaluate the acute efficacy, safety, and tolerability of lisdexamfetamine dimesylate (LDX) vs placebo (PBO) in preschool-aged children with attention-deficit/hyperactivity disorder (ADHD). METHOD: This phase 3, double-blind, fixed-dose study randomly assigned children (aged 4-5 years) with ADHD to 6 weeks of LDX (5, 10, 20, 30 mg) or PBO. The prespecified primary (change from baseline at week 6 in ADHD Rating Scale IV, Preschool version, total score [ADHD-RS-IV-PS-TS]) and key secondary (Clinical Global Impression-Improvement [CGI-I] score at week 6) efficacy endpoints were assessed using linear mixed-effects models for repeated measures. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and changes in pulse and blood pressure (BP). RESULTS: The study comprised 199 participants randomly asigned 5:5:5:5:6 to receive 5, 10, 20, 30 mg LDX or PBO, respectively. Least squares (LS) mean (95% CI) treatment difference at week 6 between pooled LDX (10, 20, 30 mg) and PBO was statistically significant for ADHD-RS-IV-PS-TS change (-5.9 [-11.01, -0.78], p = .0242; effect size [ES], -0.43). CGI-I scores improved (ie, 1-2 on CGI-I) in 41.7% for pooled LDX and 24.3% for PBO (p = .0857). The LS mean (95% CI) treatment difference between pooled LDX and PBO for CGI-I score at week 6 was -0.6 (-1.03, -0.16; p = .0074; ES, -0.52). Frequency of TEAEs was 46.6% across all 4 LDX doses vs 42.2% with PBO; the most frequent TEAEs were decreased appetite (13.7% vs 8.9%, respectively) and irritability (9.6% vs 0%). Discontinuations because of TEAEs were 5.5% for all LDX doses and 4.4% for PBO. Mean ± SD pulse/BP changes from baseline at week 6/early termination were numerically greater with LDX vs PBO (pulse beats/min: 2.7 ± 10.79 vs 1.2 ± 9.90; systolic BP, mm Hg: 1.0 ± 7.51 vs 0.3 ± 6.06; diastolic BP, mm Hg: 1.7 ± 5.90 vs 0.0 ± 6.88). CONCLUSION: In children aged 4 to 5 years with ADHD, LDX was more efficacious than PBO in reducing symptoms. The observed ES for change in ADHD-RS-IV-PS-TS appears to be smaller in magnitude than has been reported for studies of LDX conducted in older children and adolescents. LDX was generally well tolerated, and no new safety signals were identified. CLINICAL TRIAL REGISTRATION INFORMATION: Safety and Efficacy Study in Preschool Children Aged 4-5 Years With Attention-Deficit/Hyperactivity Disorder; http://www. CLINICALTRIALS: gov; NCT03260205.

A Long-Term, Open-Label Safety and Tolerability Study of Lisdexamfetamine Dimesylate in Children Aged 4-5 Years with Attention-Deficit/Hyperactivity Disorder.

Objective: To evaluate the long-term safety and tolerability of lisdexamfetamine dimesylate (LDX) in preschool-aged children (4-5 years of age inclusive) diagnosed with attention-deficit/hyperactivity disorder (ADHD). Methods: This phase 3 open-label study (ClinicalTrials.gov registry: NCT02466386) enrolled children aged 4-5 years meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for a primary ADHD diagnosis and having baseline ADHD Rating Scale-IV Preschool version total scores (ADHD-RS-IV-PS-TS) ≥24 for girls or ≥28 for boys and baseline Clinical Global Impressions-Severity scores ≥4. Participants were directly enrolled or enrolled after completing one of two antecedent short-term LDX studies. Over 52 weeks of treatment, participants received once-daily dose-optimized LDX (5-30 mg). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and vital sign changes. Clinical outcomes included ADHD-RS-IV-PS-TS changes from baseline. Results: Among 113 participants in the safety set, optimized LDX dose was 5, 10, 15, 20, and 30 mg in 1 (0.9%), 12 (10.6%), 21 (18.6%), 26 (23.0%), and 53 (46.9%) participants, respectively. Of the safety set, 69 participants (61.1%) completed the study. TEAEs were reported in 76.1% of participants; no serious TEAEs were reported. Only one type of TEAE was reported in >10% of participants (decreased appetite, 15.9%). Mean ± standard deviation (SD) changes in vital signs and body weight from baseline to week 52/or early termination (ET; n = 101) were 1.9 ± 7.73 mmHg for systolic blood pressure, 3.1 ± 7.58 mmHg for diastolic blood pressure, 4.7 ± 11.00 bpm for pulse, and 0.6 ± 1.38 kg for body weight. Over the course of the study, mean ± SD change in ADHD-RS-IV-PS-TS from baseline to week 52/ET was -24.2 ± 13.34 (n = 87). Conclusions: In this long-term 52-week study of children aged 4-5 years with ADHD, dose-optimized LDX (5-30 mg) was well tolerated and associated with reductions from baseline in ADHD symptoms.

Efficacy and Safety of Febuxostat Extended and Immediate Release in Patients With Gout and Renal Impairment: A Phase III Placebo-Controlled Study.

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.

Efficacy and safety of febuxostat extended release and immediate release in patients with gout and moderate renal impairment: phase II placebo-controlled study.

BACKGROUND: Febuxostat immediate release (IR), a xanthine oxidase inhibitor, is indicated for the management of hyperuricemia in patients with gout by lowering urate levels. An extended release (XR) formulation of febuxostat was developed to provide equal or superior efficacy on urate lowering compared with the IR formulation and potentially lower the risk of treatment-initiated gout flares due to an altered pattern of drug exposure. The present study evaluated the efficacy and safety of febuxostat XR and IR formulations in patients with gout and moderate renal impairment (estimated glomerular filtrate rate ≥ 30 and < 60 ml/min). METHODS: This was an exploratory, 3-month, phase II, multicenter, placebo-controlled, double-blind proof-of-concept study. Patients (n = 189) were randomized 1:1:1:1:1 to receive placebo or febuxostat IR 40 mg, XR 40 mg, IR 80 mg, or XR 80 mg once daily. Endpoints included: proportion of patients with serum uric acid (sUA) < 5.0 mg/dl at month 3 (primary endpoint), proportion of patients with sUA < 6.0 mg/dl at month 3, and proportion of patients with ≥ 1 gout flare requiring treatment over 3 months. RESULTS: At month 3, all febuxostat treatment groups were associated with greater proportions of patients achieving sUA < 5.0 mg/dl (p < 0.05 vs placebo). A greater proportion of patients receiving XR 40 mg achieved sUA < 5.0 mg/dl versus those receiving IR 40 mg (p = 0.034); proportions were similar in the IR 80 mg and XR 80 mg groups. Higher proportions of febuxostat-treated patients achieved sUA < 6.0 mg/dl at month 3 (p < 0.05 vs placebo) and experienced ≥ 1 gout flare (significant for all comparisons, except XR 40 mg). Incidences of treatment-related adverse events were low across all treatment groups; the majority were mild or moderate with no apparent trends correlating with IR or XR doses. The most common treatment-emergent adverse event was hypertension. One death (unrelated to the study drug) was reported. CONCLUSIONS: These exploratory data demonstrate that febuxostat (XR and IR) formulations were effective and well tolerated in patients with gout and moderate renal impairment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02128490 Registered on 29 April 2014.

Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout.

BACKGROUND: Cardiovascular risk is increased in patients with gout. We compared cardiovascular outcomes associated with febuxostat, a nonpurine xanthine oxidase inhibitor, with those associated with allopurinol, a purine base analogue xanthine oxidase inhibitor, in patients with gout and cardiovascular disease. METHODS: We conducted a multicenter, double-blind, noninferiority trial involving patients with gout and cardiovascular disease; patients were randomly assigned to receive febuxostat or allopurinol and were stratified according to kidney function. The trial had a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization). RESULTS: In total, 6190 patients underwent randomization, received febuxostat or allopurinol, and were followed for a median of 32 months (maximum, 85 months). The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up. In the modified intention-to-treat analysis, a primary end-point event occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P=0.002 for noninferiority). All-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). The results with regard to the primary end point and all-cause and cardiovascular mortality in the analysis of events that occurred while patients were being treated were similar to the results in the modified intention-to-treat analysis. CONCLUSIONS: In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events. All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. (Funded by Takeda Development Center Americas; CARES ClinicalTrials.gov number, NCT01101035 .).

Effect of Febuxostat on Ambulatory Blood Pressure in Subjects With Hyperuricemia and Hypertension: A Phase 2 Randomized Placebo-Controlled Study.

BACKGROUND: Hyperuricemia is associated with hypertension, with elevated serum uric acid levels postulated to have a causal role in the development of hypertension. Consequently, serum uric acid reduction may help lower blood pressure (BP). A Phase 2, double-blind, placebo-controlled trial was conducted to assess the potential BP-lowering effects of the xanthine oxidase inhibitor febuxostat in subjects with hypertension and hyperuricemia (serum uric acid ≥0.42 mmol/L [≥7.0 mg/dL]). METHODS AND RESULTS: Subjects (n=121) were randomized 1:1 to febuxostat 80 mg once daily or to placebo. The primary end point was change from baseline to Week 6 in 24-hour mean ambulatory systolic BP (SBP). Additional end points included the following: change from baseline to Week 3 in 24-hour mean SBP and changes from baseline to Weeks 3 and 6 in 24-hour mean ambulatory diastolic BP, serum uric acid, mean daytime and nighttime ambulatory SBP/diastolic BP, and clinic SBP/diastolic BP. For the overall study population, there were no significant differences between febuxostat and placebo for changes from baseline to Weeks 3 or 6 in ambulatory, daytime or nighttime, or clinic SBP or diastolic BP. However, in a preplanned subgroup analysis, there was a significant decrease in SBP from baseline to Week 6 in subjects with normal renal function (estimated glomerular filtration rate ≥90 mL/min) treated with febuxostat versus placebo; least squares mean difference, -6.7; 95% confidence interval -13.3 to -0.0; P=0.049. CONCLUSIONS: This study suggests that febuxostat may lower BP in hyperuricemic patients with hypertension and normal renal function; further studies should be conducted to confirm this finding. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01496469.

Effects of Febuxostat in Early Gout: A Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: To assess the effect of treatment with febuxostat versus placebo on joint damage in hyperuricemic subjects with early gout (1 or 2 gout flares). METHODS: In this double-blind, placebo-controlled study, 314 subjects with hyperuricemia (serum uric acid [UA] level of ≥7.0 mg/dl) and early gout were randomized 1:1 to receive once-daily febuxostat 40 mg (increased to 80 mg if the serum UA level was ≥6.0 mg/dl on day 14) or placebo. The primary efficacy end point was the mean change from baseline to month 24 in the modified Sharp/van der Heijde erosion score for the single affected joint. Additional efficacy end points included change from baseline to month 24 in the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) scores for synovitis, erosion, and edema in the single affected joint, the incidence of gout flares, and serum UA levels. Safety was assessed throughout the study. RESULTS: Treatment with febuxostat did not lead to any notable changes in joint erosion over 2 years. In both treatment groups, the mean change from baseline to month 24 in the modified Sharp/van der Heijde erosion score for the single affected joint was minimal, with no between-group differences. However, treatment with febuxostat significantly improved the RAMRIS synovitis score at month 24 compared with placebo treatment (change from baseline -0.43 versus -0.07; P <0.001), decreased the overall incidence of gout flares (29.3% versus 41.4%; P < 0.05), and improved serum UA control (62.8% versus 5.7%; P < 0.001). No major safety concerns were reported. CONCLUSION: Urate-lowering therapy with febuxostat improved magnetic resonance imaging-determined synovitis and reduced the incidence of gout flares in subjects with early gout.

Impact of Febuxostat on Renal Function in Gout Patients With Moderate-to-Severe Renal Impairment.

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 m(2) ). 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.

Randomized controlled trial of febuxostat versus allopurinol or placebo in individuals with higher urinary uric acid excretion and calcium stones.

BACKGROUND AND OBJECTIVES: Higher urinary uric acid excretion is a suspected risk factor for calcium oxalate stone formation. Febuxostat, a xanthine oxidoreductase inhibitor, is effective in lowering serum urate concentration and urinary uric acid excretion in healthy volunteers and people with gout. This work studied whether febuxostat, compared with allopurinol and placebo, would reduce 24-hour urinary uric acid excretion and prevent stone growth or new stone formation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this 6-month, double-blind, multicenter, randomized controlled trial, hyperuricosuric participants with a recent history of calcium stones and one or more radio-opaque calcium stone ≥ 3 mm (as seen by multidetector computed tomography) received daily febuxostat at 80 mg, allopurinol at 300 mg, or placebo. The primary end point was percent change from baseline to month 6 in 24-hour urinary uric acid. Secondary end points included percent change from baseline to month 6 in size of index stone and change from baseline in the mean number of stones and 24-hour creatinine clearance. RESULTS: Of 99 enrolled participants, 86 participants completed the study. Febuxostat led to significantly greater reduction in 24-hour urinary uric acid (-58.6%) than either allopurinol (-36.4%; P=0.003) or placebo (-12.7%; P<0.001). Percent change from baseline in the size of the largest calcium stone was not different with febuxostat compared with allopurinol or placebo. There was no change in stone size, stone number, or renal function. No new safety concerns were noted for either drug. CONCLUSIONS: Febuxostat (80 mg) lowered 24-hour urinary uric acid significantly more than allopurinol (300 mg) in stone formers with higher urinary uric acid excretion after 6 months of treatment. There was no change in stone size or number over the 6-month period.

Preservation of renal function during gout treatment with febuxostat: a quantitative study.

BACKGROUND: Hyperuricemia can accelerate renal decline associated with aging. Chronic kidney disease is frequently seen in patients with hyperuricemia and gout. OBJECTIVES: Assess the impact of urate-lowering therapy on renal function in subjects with gout who were treated with febuxostat for ≤ 48 months. METHODS: Subjects from 2 phase 3 clinical studies were enrolled in the phase 3, long-term, open-label Febuxostat/Allopurinol Comparative Extension Long-Term (EXCEL) study. In the EXCEL study, 1086 subjects initially were treated with febuxostat 80 or 120 mg daily, or allopurinol 300 mg daily. The subjects were permitted to switch between doses of febuxostat and/or allopurinol during the first 6 months of treatment to achieve and maintain a serum uric acid (SUA) level ≥ 3 to < 6 mg/dL. For the analysis presented in this article, data from 551 subjects who received only febuxostat throughout the duration of both the phase 3 and EXCEL studies (≤ 48 months) were used to determine the impact of SUA reduction on estimated glomerular filtration rates (eGFRs). RESULTS: At baseline of the 2 original phase 3 studies, subjects' mean SUA level was 9.8 mg/dL. Greater sustained decreases in subjects' SUA levels were associated with less renal function decline (P < 0.001) by statistical modeling. The study data predicted that for every 1 mg/dL of chronic reduction of SUA level in subjects with gout, there would be a preservation of 1.15 mL/min of eGFR. CONCLUSION: Sustained urate-lowering therapy with febuxostat appears to impede renal decline in patients with gout. The results discussed in this article support similar observations previously reported in 116 hyperuricemic subjects with gout who received febuxostat for ≤ 5 years.

The effects of xanthine oxidase inhibition by febuxostat on the pharmacokinetics of theophylline.

OBJECTIVE: Febuxostat, a non-purine selective xanthine oxidase (XO) inhibitor, may affect the metabolism of theophylline as XO hydroxylates 1-methylxanthine to 1-methyluric acid. The objective of this study was to examine the effects of febuxostat on the pharmacokinetics of theophylline and its metabolites. METHODS: 24 healthy subjects received febuxostat 80 mg (Regimen A) or matching placebo (Regimen B) daily for 7 days along with a single oral dose of theophylline 400 mg on Day 5 in a double-blind, randomized, cross-over fashion (≥ 7 day washout between periods) followed by collection of plasma and urine samples for 72 h. RESULTS: For Regimens A and B, mean theophylline Cmax values were 4.4 and 4.1 µg/ml, respectively, and mean theophylline AUC0-tlqc was 122.3 and 115.2 µg x h/ml, respectively. The ratios of theophylline Cmax and AUC0-tlqc central values following coadministration with febuxostat or placebo were 1.03 (90% confidence intervals (CIs), 0.917 - 1.149) and 1.04 (90% CI, 0.927 - 1.156). Both 90% CIs fell within the no-effect range of 0.8 and 1.25. Mean excreted amounts in urine for 1-methylxanthine levels were higher in Regimen A vs. B (40.1 vs. 0.1 mg), while 1-methyluric acid levels were lower (3.1 vs. 56.2 mg). Mean excreted amounts of theophylline and other metabolites were comparable between Regimen A and B. CONCLUSIONS: No dose adjustment for theophylline is necessary when coadministered with febuxostat 80 mg, as coadministration does not affect the plasma pharmacokinetics of theophylline and neither 1-methylxanthine nor 1-methyluric have any pharmacological effect.

Treating hyperuricemia of gout: safety and efficacy of febuxostat and allopurinol in older versus younger subjects.

Despite an increasing incidence of gout in older age patients with multiple metabolic and cardiovascular comorbidities, there are limited data addressing whether currently available urate-lowering therapy is comparably effective and safe in older (≥65 years of age) versus younger (<65 years of age) patients. In this secondary analysis of data from the CONFIRMS trial, we found that among 374 older subjects, urate-lowering therapy with approved doses of febuxostat or commonly prescribed doses of allopurinol was at least comparable to that in 1894 younger subjects and was well tolerated despite high rates of renal impairment and cardiovascular comorbidities in the older subjects.

Febuxostat in gout: serum urate response in uric acid overproducers and underexcretors.

OBJECTIVE: Hyperuricemia of gout can arise due to either overproduction or underexcretion of uric acid. Not all available urate-lowering therapies are equally effective and safe for use in patients with renal disease. The objective of this post-hoc analysis was to determine the effectiveness of the xanthine oxidase inhibitor febuxostat in reducing serum urate (sUA) levels in gouty patients who were either overproducers or underexcretors. METHODS: Gouty subjects 18 to 85 years of age with sUA ≥ 8.0 mg/dl at baseline were enrolled in a Phase 2, 28-day, multicenter, randomized, double-blind, placebo-controlled trial and randomized to receive febuxostat 40 mg, 80 mg, or 120 mg daily, or placebo. The primary efficacy endpoint was the proportion of subjects with sUA < 6.0 mg/dl at Day 28. Secondary efficacy endpoints included percentage reductions in sUA and urinary uric acid (uUA) from baseline to Day 28. RESULTS: Of the 153 subjects, 118 (77%) were underexcretors (uUA ≤ 800 mg/24 h) and 32 (21%) were overproducers (uUA > 800 mg/24 h); baseline uUA data were missing for 3 subjects. Treatment with febuxostat led to the majority of subjects achieving sUA < 6.0 mg/dl at Day 28. Treatment with any dose of febuxostat led to significantly greater percentage reductions in uUA than that observed in the placebo group, for both underexcretors and overproducers. CONCLUSION: Febuxostat is a highly efficacious urate-lowering therapy in patients with gout regardless of overproduction or underexcretion status.

Renal function in gout: long-term treatment effects of febuxostat.

BACKGROUND: The association between hyperuricemia, gout, and impaired renal function has long been recognized. Recent data provide evidence for the causal relationship between elevated serum urate (sUA) and renal changes, leading to declines in glomerular filtration rates. In healthy adults, glomerular filtration rate wanes with age. Urate-lowering therapy (ULT) with allopurinol has been shown to stabilize or reverse this. OBJECTIVE: Here we examine the long-term effects of ULT with febuxostat on estimated glomerular filtration rate (eGFR). METHODS: This is a post hoc analysis of the Febuxostat Open-label Clinical trial of Urate-lowering efficacy and Safety study, during which 116 hyperuricemic gout subjects received daily doses of febuxostat (40, 80, or 120 mg) for up to 5 years. sUA concentrations and eGFR were assessed regularly. Results were stratified by mean change in sUA from baseline. Mathematical modeling was used to predict the effect of sUA reduction on eGFR. RESULTS: Maintenance or improvement in eGFR was inversely correlated with the quantitative reduction in sUA from baseline. For every 1 mg/dL decrease in sUA, the model projected an expected improvement in eGFR of 1 mL/min from the untreated value. CONCLUSION: Individuals with the greatest reductions in sUA may experience reduced rates of renal deterioration or even stabilization of renal function. Further studies examining the impact of long-term ULT on renal function in hyperuricemic gout patients are needed to both confirm our results and verify if improvements in renal function are feasible in such patients.

Drug interaction studies with dexlansoprazole modified release (TAK-390MR), a proton pump inhibitor with a dual delayed-release formulation: results of four randomized, double-blind, crossover, placebo-controlled, single-centre studies.

BACKGROUND AND OBJECTIVE: Most proton pump inhibitors are extensively metabolized by cytochrome P450 (CYP) isoenzymes, as are many other drugs, giving rise to potential drug-drug interactions. Dexlansoprazole modified release (MR) [TAK-390MR] is a modified-release formulation of dexlansoprazole (TAK-390), an enantiomer of lansoprazole, which employs an innovative Dual Delayed Release technology designed to prolong the plasma dexlansoprazole concentration-time profile following once-daily oral administration. As with lansoprazole, dexlansoprazole is metabolized mainly by CYP3A and CYP2C19. Based on in vitro studies, dexlansoprazole has the potential to inhibit activity of these isoenzymes and also may induce human hepatic CYP1A and CYP2C9 activity. To determine whether dexlansoprazole has an effect on these isoenzymes in vivo, drug interaction studies with dexlansoprazole MR were conducted. METHODS: Four separate randomized, double-blind, two-way crossover, placebo-controlled, single-centre studies were conducted in healthy volunteers to evaluate the effect of dexlansoprazole on the pharmacokinetics of four test substrates (diazepam, phenytoin, theophylline [administered as intravenous aminophylline] and warfarin), which were selected based on in vitro and/or in vivo data that suggest a potential drug interaction with CYP isoenzymes or potentially coadministered narrow therapeutic index drugs. In each study, dexlansoprazole MR 90 mg or placebo was administered once daily for 9 or 11 days in each period. Subjects received a single dose of test substrate in each study period. Pharmacokinetic parameters of the test substrates were estimated using noncompartmental methods. A conclusion of no effect of dexlansoprazole MR on the test substrate was made if the 90% confidence intervals (CIs) for the ratios of the central values for the observed maximum plasma drug concentration (C(max)) and the area under the plasma concentration-time curve (AUC) of test substrate administered with dexlansoprazole MR versus placebo were within 0.80-1.25 based on an analysis of variance model. The potential for a pharmacodynamic interaction was also assessed for warfarin using prothrombin time, measured as the international normalized ratio. Routine safety assessments were conducted in these studies. RESULTS: Mean C(max) and AUC values were generally similar for each test substrate when administered with multiple once-daily doses of dexlansoprazole MR or placebo. The 90% CIs for the bioavailability of these test substrates administered with dexlansoprazole MR relative to that obtained when the substrates were administered with placebo were within the bioequivalency range of 0.80-1.25, indicating that multiple doses of dexlansoprazole MR had no effect on the pharmacokinetics of these drugs. Additionally, dexlansoprazole MR had no effect on the pharmacodynamics of warfarin. Administration of these drugs with dexlansoprazole MR 90 mg or placebo was well tolerated; the only serious adverse event, which led to a subject's discontinuation from the study, was considered unrelated to study drugs. CONCLUSIONS: Coadministration of dexlansoprazole MR with diazepam, phenytoin or theophylline did not affect the pharmacokinetics of these drugs, and therefore is unlikely to alter the pharmacokinetic profile of other drugs metabolized by CYP2C19, CYP2C9, CYP1A2 and perhaps CYP3A. Additionally, dexlansoprazole MR coadministered with warfarin did not affect the pharmacokinetics of the warfarin enantiomers and had no effect on the anticoagulant activity of warfarin. Dexlansoprazole MR was well tolerated in these trials of healthy subjects.