Management Of Hyperuricemia Research Articles

426: Use of low dose rasburicase in the management of hyperuricemia in tumor lysis syndrome

Background: Hyperuricemia is a complication of tumor lysis syndrome (TLS) in patients with high grade lymphomas, leukemias, and bulky tumors. Rasburicase is a recombinant form of urate oxidase which converts uric acid to a more soluble form, allantoin. It is indicated for the management of hyperuricemia in tumor lysis syndrome. City of Hope is a National Cancer Institute (NCI) designated comprehensive cancer center specializing in oncology, hematology, and hematopoietic stem cell transplantation (HSCT).

原著2高尿酸血症・痛風の治療ガイドラインに準拠した高尿酸血症管理支援コンピュータシステムを用いた健診判定について

人間ドックにおいて,受診者に事前に問診票を送付することにより得られた詳細な医療情報や,網羅的検査により診察結果,検査データを一度に収集,利用することにより,2002年に発表された高尿酸血症・痛風の治療ガイドラインに準拠し判定する高尿酸血症管理支援コンピュータシステムを構築, 運用した. まったく同一の問診情報と検査結果であっても,9人の人間ドック判定医自身の判断で尿酸値判定を行った場合,判定医毎,受診者毎に判定は大きく異なった.しかし,このシステムを利用することによって,1.判定医間,受診者間にばらつきの少ない整合性ある判定が得られ,さらに,薬物療法中の場合は,セカンドオピニオンとして治療の良否を自動的に判定できる,2.専門学会で作成されたガイドラインに基づき診断論理を作成することにより,高尿酸血症・痛風の治療ガイドラインに精通しない判定医でもよりEBMに基づいた判定が行える,3.判定医がガイドラインを学習する機会となる,4.コメント文が自動的に印字されるため医師の乱筆乱文による苦情を防げる,5.判定,コメント文の記載が自動化されることにより,医師業務の省力化が図れる,などの利点が考えられた.

New developments in clinically relevant mechanisms and treatment of hyperuricemia

The prevalence of gout has increased markedly in the United States in the past two decades, and new treatments for hyperuricemia are being developed. Recent molecular identification of urate transporter-1 (URAT1) as the central mediator of renal urate reabsorption has provided novel understanding of the pathogenesis of hyperuricemia, and the target site for current and possibly future primary uricosuric agents. Recent studies have also highlighted uricosuric effects of several drugs (losartan, atorvastatin, fenofibrate) that are prescribed for primary indications other than hyperuricemia. The niche of these agents in current management of hyperuricemia is discussed. We also review the ongoing development of recombinant uricase preparations and of novel xanthine oxidase inhibitors exemplified by febuxostat. These agents should provide novel options for patients with chronic, refractory gout and hyperuricemia, particularly in association with allopurinol hypersensitivity and renal insufficiency.

Pharmacokinetics, Pharmacodynamics and Safety of Febuxostat, a Non-Purine Selective Inhibitor of Xanthine Oxidase, in a Dose Escalation Study in Healthy Subjects

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase currently being developed for the management of hyperuricemia in patients with gout. To investigate the pharmacokinetics, pharmacodynamics and safety of febuxostat over a range of oral doses in healthy subjects. In a phase I, dose-escalation study, febuxostat was studied in dose groups (10, 20, 30, 40, 50, 70, 90, 120, 160, 180 and 240 mg) of 12 subjects each (10 febuxostat plus 2 placebo). In all groups, subjects were confined for 17 days and were administered febuxostat once daily on day 1, and days 3-14. During the course of the study, blood and urine samples were collected to assess the pharmacokinetics of febuxostat and its metabolites, and its pharmacodynamic effects on uric acid, xanthine and hypoxanthine concentrations after both single and multiple dose administration. Safety measurements were also obtained during the study. Orally administered febuxostat was rapidly absorbed with a median time to reach maximum plasma concentration following drug administration of 0.5-1.3 hours. The pharmacokinetics of febuxostat were not time dependent (day 14 vs day 1) and remained linear within the 10-120 mg dose range, with a mean apparent total clearance of 10-12 L/h and an apparent volume of distribution at steady state of 33-64 L. The harmonic mean elimination half-life of febuxostat ranged from 1.3 to 15.8 hours. The increase in the area under the plasma concentration-time curve of febuxostat at doses >120 mg appeared to be greater than dose proportional, while the febuxostat maximum plasma drug concentration was dose proportional across all the doses studied. Based on the urinary data, febuxostat appeared to be metabolised via glucuronidation (22-44% of the dose) and oxidation (2-8%) with only 1-6% of the dose being excreted unchanged via the kidneys. Febuxostat resulted in significant decreases in serum and urinary uric acid concentrations and increases in serum and urinary xanthine concentrations. The percentage decrease in serum uric acid concentrations ranged from 27% to 76% (net change: 1.34-3.88 mg/dL) for all doses and was dose linear for the 10-120 mg/day dosage range. The majority of adverse events were mild-to-moderate in intensity. Febuxostat was well tolerated at once-daily doses of 10-240 mg. There appeared to be a linear pharmacokinetic and dose-response (percentage decrease in serum uric acid) relationship for febuxostat dosages within the 10-120 mg range. Febuxostat was extensively metabolised and renal function did not seem to play an important role in its elimination from the body.

Rasburicase: A New Approach for Preventing and/or Treating Tumor Lysis Syndrome

Tumor lysis syndrome (TLS) is an oncologic emergency requiring prompt attention to the management of potentially life-threatening metabolic derangements. Hyperuricaemia is one of the prominent features of TLS which, if not adequately prevented or treated, may lead to renal failure, requiring dialysis. Conventional management of hyperuricaemia involved the use of aggressive hydration, urinary alkalinization and allopurinol. Despite these measures, as many as 14.1% of high-risk patients may still develop renal failure. With the advent of newer agents such as rasburicase, the paradigm of TLS management has shifted towards risk stratification and the use of rasburicase in conjunction with hydration in patients at high risk for TLS. The advantage of rasburicase over allopurinol is its rapid onset of action, lack of need for urine alkalinization, which may worsen hyperphosphataemia and a satisfactory safety profile. Overall, rasburicase offers a safe and more effective alternative to allopurinol in patients at highest risk for TLS. Some of the unanswered questions requiring further investigation with regard to rasburicase use include the optimal number of doses needed, optimal dose based on uric acid levels and tumor burden, dosing in obese patients and maximum dose.

Febuxostat: a non-purine, selective inhibitor of xanthine oxidase for the management of hyperuricaemia in patients with gout

Febuxostat is a non-purine, selective inhibitor of xanthine oxidase being developed for the management of hyperuricaemia in patients with gout. With febuxostat 10 – 120 mg, the pharmacokinetics are linear. No dose adjustment appears to be necessary in those with renal insufficiency or mild-to-moderate hepatic impairment. Febuxostat 10 – 120 mg/day rapidly and sustainably reduces serum uric acid by 25 – 70% in uric acid underexcretors and overproducers. Prophylaxis with colchicine or a non-steroidal anti-inflammatory drug can mitigate the gout-flare risk from the rapid urate lowering after febuxostat initiation. Febuxostat is well tolerated, the majority of treatment-related adverse events are transient and mild-to-moderate in severity. Febuxostat can broaden the therapeutic options for urate-lowering therapy in those with gout.

Management of Hyperuricemia with Rasburicase Review

Tumor lysis syndrome (TLS) is a serious complication in patients with hematological malignancies. Massive lysis of tumor cells can lead to hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcaemia. These metabolic disturbances may result in renal failure, because of precipitation of uric acid crystals and calcium phosphate salts in the kidney. The standard prophylaxis or treatment of hyperuricemia consists of decreasing uric acid production with allopurinol and facilitating its excretion by urinary alkalinization and hyperhydration. By inhibiting the enzyme xanthine oxidase, allopurinol blocks the conversion of hypoxanthine and xanthine into uric acid. An alternative treatment is urate oxidase which oxidates uric acid into allantoin. Allantoin is 5-10 times more soluble than uric acid and is therefore excreted easily. In several clinical trials rasburicase, the recombinant form of urate oxidase, has shown to be very effective in preventing and treating hyperuricemia. Rasburicase, in contrast with the non-recombinant form of urate oxidase uricozyme, is associated with a low incidence of hypersensitivity reactions. In addition to the demonstrated clinical benefit, rasburicase also proved to be a cost-effective option in the management of hyperuricemia.

Effect of febuxostat on pharmacokinetics of desipramine, a CYP2D6 substrate, in healthy subjects

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase (NP-SIXO) being developed for the management of hyperuricemia in patients with gout. Background In-vitro data showed that febuxostat had no significant effect on CYP1A2, CYP2C9, CYP2C19 or CYP3A4 activity (Ki>100 μM), and a weak inhibitory effect on CYP2D6 (Ki=40 μM). Aim The effect of febuxostat on desipramine pharmacokinetics (PK) was evaluated. Methods A phase-1, two-period, crossover, double-blind study was conducted in 18 CYP2D6 extensive-metabolizer subjects. Each subject received a single 25 mg oral dose of desipramine (DES) after multiple oral dosing with febuxostat (FBX) 120 mg or placebo (PLA) once daily. Blood samples were collected to assess the PK of DES and 2-hydroxydesipramine (2-HD). Results The results are shown in the table below. The increase in total exposure to DES and the concomitant decrease in the 2-HD/DES AUC ratio suggest that the metabolism of DES to 2-HD via CYP2D6 was mildly inhibited. However, this effect was not considered to be clinically significant. The incidence of adverse events was similar between treatment regimens with the majority being mild and moderate in severity. Conclusion No dose adjustment is expected for CYP2D6 substrates when co-administered with febuxostat. Clinical Pharmacology & Therapeutics (2005) 77, P43–P43; doi: 10.1016/j.clpt.2004.12.059 Table 1. Mean±SD Plasma PK for DES and 2-HD, Point Estimates (PE) and Confidence Intervals (CI) Parameter DES + FBX DES + PLA PE (90% CI)1 1 Ratio of DES+FBX to DES+PLA 2 AUC Ratio: 2-HD/DES AUC ratio DES Cmax (ng/mL) 9.6 ± 3.5 8.4 ± 3.2 1.16 (1.10–1.23) AUC∞ (ng h/mL) 295 ± 194 263 ± 249 1.22 (1.11–1.35) 2-HD Cmax (ng/mL) 6.2 ± 2.0 6.6 ± 2.3 0.96 (0.90–1.02) AUC∞ (ng h/mL) 163 ± 30 166 ± 62 1.02 (0.93–1.11) AUC Ratio2 0.74 ± 0.40 0.88 ± 0.49 0.83 (0.76–0.91}

Effect of food or antacid on febuxostat pharmacokinetics and pharmacodynamics in healthy subjects

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase (NP-SIXO) being developed for the management of hyperuricemia in patients with gout. Aim The effects of food and antacid on oral febuxostat pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated. Methods In 4 phase-1, two-period, crossover studies, male and female subjects received either a single dose (SD) of 40 mg (n=23) or 120 mg (n=19), or multiple dose (MD) 80 mg daily for 6 days (n=23) of febuxostat under non-fasting[test (T)] and fasting[reference (R)] conditions; or received a single 80 mg dose with (T) and without (R) an antacid (800 mg Mg(OH)2-900 mg Al(OH)3). Plasma febuxostat (LC-MS/MS method) and serum uric acid (sUA, PD marker, enzymatic assay) concentrations were assessed. Results A delay of tmax was observed with both food and antacid. Point estimates (PE) and confidence intervals (CI) for T and R ratios/differences are shown below for febuxostat Cmax, AUC and sUA 24-hour mean concentration (Cmean,24). (see Table) Even though food caused a decrease in the absorption rate and extent of febuxostat in all food effect studies, this decrease was not associated with a decrease in febuxostat PD effect (sUA), when evaluated in the 80 mg MD study. Despite a decrease in the absorption rate of febuxostat, antacid had no effect on the extent of febuxostat absorption. Febuxostat was safe and well tolerated in all studies. Conclusion Febuxostat can be administered regardless of food or antacid intake. Clinical Pharmacology & Therapeutics (2005) 77, P50–P50; doi: 10.1016/j.clpt.2004.12.083 Febuxostat Dose Febuxostat Cmax Febuxostat AUC1 Cmean,24 (%) Food Effect 40 mg SD 0.54 (0.48–0.61)2 0.81 (0.77–0.85)2 - 80 mg MD 0.51 (0.44–0.60)2 0.82 (0.78–0.87)2 6 (4–10) 120 mg SD 0.62 (0.52–0.74)2 0.84 (0.79–0.90)2 - Antacid Effect 80 mg SD 0.68 (0.58–0.79)2 0.85 (0.81–0.90)2 - 1 AUC∞[single dose (SD)] or AUC24[multiple dose (MD)] 2 T/R ratio PE (90% CI, log-transformed data) for febuxostat PK parameter ratios T-R difference PE (95% CI) for the % change from the baseline in Cmean,24

Effects of age and gender on febuxostat pharmacokinetics, pharmacodynamics, and safety in healthy subjects

Background Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase (NP-SIXO) being developed for the management of hyperuricemia in patients with gout. Aim The effects of age and gender on the pharmacokinetics (PK), pharmacodynamics (PD), and safety of febuxostat were evaluated. Methods In a phase-1, parallel group, open-label, multiple dose study, male (M) and female (F) subjects between 19–40 years old[young (Y), 12M/12F] and 65–76 years old[elderly (E), 12M/12F] received once daily 80 mg oral doses of febuxostat for 7 days. Blood samples were collected to assess the PK of febuxostat and its active metabolites (67M-1, 67M-2, 67M-4) as well as its effect on uric acid (PD marker). Protein binding and safety of febuxostat were also assessed. Results The results are shown in the table below. The overall incidence of study drug related adverse events (AEs) was lower in M than in F (13% vs 54%) and in Y than in E (25% vs 42%). The most common AEs were headache and constipation. The majority of AEs were mild in severity. Conclusion Neither age nor gender had any clinically significant effect on the PK, PD, and safety of febuxostat. Therefore, febuxostat does not require any dose adjustment based on age or gender. Clinical Pharmacology & Therapeutics (2005) 77, P50–P50; doi: 10.1016/j.clpt.2004.12.084 Table 1. Mean± SD Plasma Pharmacokinetic and Serum Uric Acid (sUA) Parameters on Day 7 Age Gender Analyte Parameter Y E M F Febuxostat Cmax,u (ng/mL) 28±12 27±9 24±10 31±101,2 AUC24,u (ng·h/mL) 56±19 61±20 54±23 63±151,2 fu (%) 0.7±0.1 0.7±0.2 0.7±0.1 0.7±0.1 67M-1 AUC24 (ng·h/mL) 225±63 265±84 224±68 265±80 67M-2 AUC24 (ng·h/mL) 229±76 243±69 240±81 232±63 67M-4 AUC24 (ng·h/mL) 235±77 270±125 223±70 281±125 sUA Cmean,24 (%change) −55±8 −56±9 −52±7 −59±81 Cmax,u or AUC24,u: Unbound Cmax or AUC24; fu: Unbound fraction; Cmean,24: sUA 24-hour mean concentration; 1 Statistically significantly different from M (p≤ 0.05) 2 Not statistically significantly different from M (p>0.05) with weight as a covariate

Parecoxib, Valdecoxib, and Cardiovascular Risk

Selective inhibitors of cyclooxygenase (COX)-21 depress prostacyclin (PGI2) but not COX-1–derived thromboxane A2. The effects of thromboxane A2 would be exaggerated during treatment with COX-2 inhibitors, potentially predisposing patients to heart attack and stroke.2 A randomized controlled trial in patients undergoing coronary artery bypass graft (CABG) surgery and receiving either placebo or 40 mg parecoxib (Dynastat; Pfizer), the intravenously administered prodrug of valdecoxib (Bextra; Pfizer), followed by oral valdecoxib 40 mg BID for 14 days, revealed a cluster of cardiovascular events.3 In a second study, one group received parecoxib/valdecoxib, another …

代謝・栄養疾患としての高尿酸血症・痛風とプリンヌクレオチド／尿酸代謝

Hyperuricemia and gout are included among such lifestyle-related diseases as obesity, diabetes, hypertension and dyslipidemia. Hyperuricemia involves the serum urate level exceeding the solubility limit, the resulting crystallized urate deposits causing gouty arthritis and a renal disorder induced by gout. Uric acid is an end product of purine nucleotide degradation. This review summarizes recent biochemical and molecular biological data from principally Japanese studies on purine nucleotide biosynthesis, uric acid formation and its renal excretion. The Japanese Society of Gout and Nucleic Acid Metabolism published in 2001 guidelines for the management of hyperuricemia and gout in order to standardize the diagnosis and therapy of these disorders. These guidelines define hyperuricemia as a urate concentration of over 7mg/dl in the blood, indicating the solubility limit based on the physicochemical properties of urate. The required change of patients' lifestyles, including dietary habits, is also reviewed

Management of Hyperuricemia with Rasburicase Review

Tumor lysis syndrome (TLS) is a serious complication in patients with hematological malignancies. Massive lysis of tumor cells can lead to hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcaemia. These metabolic disturbances may result in renal failure, because of precipitation of uric acid crystals and calcium phosphate salts in the kidney. The standard prophylaxis or treatment of hyperuricemia consists of decreasing uric acid production with allopurinol and facilitating its excretion by urinary alkalinization and hyperhydration. By inhibiting the enzyme xanthine oxidase, allopurinol blocks the conversion of hypoxanthine and xanthine into uric acid. An alternative treatment is urate oxidase which oxidates uric acid into allantoin. Allantoin is 5–10 times more soluble than uric acid and is therefore excreted easily. In several clinical trials rasburicase, the recombinant form of urate oxidase, has shown to be very effective in preventing and treating hyperuricemia. Rasburicase, in contrast with the non‐recombinant form of urate oxidase uricozyme, is associated with a low incidence of hypersensitivity reactions. In addition to the demonstrated clinical benefit, rasburicase also proved to be a cost‐effective option in the management of hyperuricemia.

A single dose of rasburicase is sufficient for the treatment of hyperuricemia in patients receiving chemotherapy

Hydration, urinary alkalization, and allopurinol are the standard of care in the treatment and prevention of hyperuricemia. Rasburicase is a new alternative for the management of hyperuricemia in cancer patients. Criteria for the use of rasburicase were developed by the Hematology/Oncology Pharmacy and Therapeutics Subcommittee of the Detroit Medical Center and implemented in 2003. The guidelines limit rasburicase use to one dose, with additional doses as needed, compared to the five doses recommended by the manufacturer, in cancer patients with hyperuricemia and bulky tumor who require immediate chemotherapy. During the period of March to September 2003, eight patients received rasburicase, according to the guidelines, for the management of hyperuricemia. One dose of rasburicase produced a rapid and sustained therapeutic effect of lowering the plasma uric acid levels in all patients. The levels remained below 4 mg/dL throughout the administration of chemotherapy for up to 96 h. Utilizing the guidelines resulted in a significant cost savings of US$ 100,000.

Serum uric acid-lowering therapies: where are we heading in management of hyperuricemia and the potential role of uricase.

Although allopurinol has been available for approximately 50 years, hyperuricemia and its sequelae are not only prevalent, but the incidence and costs associated with this disorder continue to increase. However, several new therapies have been developed. Recombinant urate oxidase has been useful in the treatment of tumor lysis hyperuricemia, and pegylated urate oxidase shows promise in patients with hyperuricemia and gout. Febuxostat and Y-700 are new oral xanthine oxidase inhibitors that are in human clinical trials. Tailoring of antilipid therapy in selected hyperuricemic and hyperlipidemic patients with fenofibrate may be of benefit in lowering blood cholesterol and uric acid levels. Similarly, treatment of selected hyperuricemic patients who also are hypertensive with losartan or amlodipine may be beneficial in lowering blood pressure and hyperuricemia. Despite these advances, new treatments for hyperuricemia are needed.

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In 1996, the need for the clinical guidelines for the management of hyperuricemia and gout was proposed of the consensus conference held at the 29th annual meeting of the Japanese Society of Purine and Pyrimidine Metabolism (president Yuji Matsuzawa). At the consensus conference, the following announcement was made. 1. Because the majority of patients with hyperuricemia are in the condition of multiple risk factor clustering syndrome, hyperuricemia per se should be counted as one of the typical lifestyle related diseases. 2. Medical management should be directed independently for the treatment of gouty arthritis and for control of the serum uric acid level. 3. The serum uric acid level should be taken into account as a possible cardiovascular risk factor. 4. Urine alkalization should be started if there is no symptom indicating hyperuricemia for the prophylaxis of urinary stones and renal dysfunction. 5. All the medical management should be considered under the consensus of the many expert physicians dealing with hyperuricemia and gout. This principal announcement was made by the consensus conference and the simple management recommendation of a 6-7-8 rule was proposed through the consensus of expert physicians. Recently, a guideline committee was organized in the Japanese Society of Gout and Nucleic Acid Metabolism (previous by the Japanese Society of Purine and Pyrimidine Metabolism) and the Guidelines for the Management of Hyperuricemia and Gout were prereleased in February and published in August 2002. In the new guidelines, the above policy was introduced and evidence was collected to give the guidelines contemporary clinical usefulness and value. It will help in the proper management of hyperuricemia in apparently healthy persons in occupational health, having multiple risk factors.

The management of hyperuricemia and gout in patients with heart failure.

The management of hyperuricemia and gout in patients with heart failure.

Role of intravenous allopurinol in the management of acute tumor lysis syndrome

In conclusion, the data available to date appear to show that IV allopurinol is safe and effective in the management of hyperuricemia associated with malignancy whether used prophylactically or therapeutically. However, randomized, controlled clinical trials would be needed to precisely define the success rates reported in the open-label, compassionate use studies. There are a subset of patients who absolutely require and will benefit from an IV formulation of allopurinol. Although the pharmacokinetics of the oral and IV forms are relatively comparable in normal healthy volunteers, it is not definitively known to what extent the pharmacokinetic parameters (specifically, bioavailablity) of the oral formulation might be altered in the critically ill patient experiencing ATLS. Controlled trials in these patients, for whom allopurinol is indicated, comparing pharmacokinetic parameters of oral and IV forms are warranted. In the interim, a subset of patients unable to use oral dosage forms, regardless of rationale, will benefit from the recent routine availability of IV allopurinol.

高尿酸血症管理の最近の動向について-実地医家調査1996年と1999年の相違点の分析から.

common diseaseである, 痛風・高尿酸血症診療に広く実地医家の参加を求め, 診療の均質化をはかることを目的に, 1996年の第29回日本プリン・ピリミジン代謝学会総会でコンセンサス・カンファランスが開催された. 著者らはここで,現在「6-7-8のルール」と称している尿酸管理基準に関する提言を行い, 当時の専門医と実地医家による高尿酸血症管理の現状調査から,いくつかの問題点を指摘してきた.今回,コンセンサス・カンファランスから3年を経過したのを契機に, 再度実地医家に対する調査を実施した. 1999年末までの段階では,実地医家による尿酸値の管理の現状は, 大筋でコンセンサス・カンファランスでの提言に近いものへ変化が認められた. しかるに尿路管理の考え方や病型分類に基づく適切な薬剤の選択の有無などの点で, 専門医の是とするものからの隔たりが存在した. 注目すべき点は,高尿酸血症をマルチプルリスクの一部ととらえる考え方の浸透度が高いことであった. 今後は,いわゆる無症候性であっても,高尿酸血症を治療することが是であるか否かのevidenceを専門医集団の努力で提示していく必要があると考えられた.

Broadsheet number 43: The role of the laboratory in the investigation and management of hyperuricemia

Broadsheet number 43: The role of the laboratory in the investigation and management of hyperuricemia