Lhanoo Gunawardhana

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.

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.

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

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).

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.

AbstractBackground 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 (Cmax) 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 Cmax 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.

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. Allcause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. (Funded by Takeda Development Center Americas; CARES ClinicalTrials.gov number, NCT01101035.)

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.

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

To assess the effect of treatment with febuxostat versus placebo on joint damage in hyperuricemic subjects with early gout (1 or 2 gout flares).

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.

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.

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.