Rasburicase: future directions in tumor lysis management

Acute tumor lysis syndrome (TLS) is an oncologic emergency resulting in several metabolic derangements. Hyperuricemia and its associated complications are the most frequent manifestations of TLS. Crucial to the management is the prompt initiation of a hypouricemic agent such as rasburicase. An established dose of 0.2 mg/kg of rasburicase is effective at decreasing uric acid levels significantly in 4 h of administration and to undetectable levels in 48 h of initiation. The mean uric acid AUC is significantly lower for patients treated with rasburicase when compared to those receiving allopurinol. Rasburicase has demonstrated excellent tolerability and is potentially cost-effective in patients at high risk for TLS. Rasburicase is a safe and effective hypouricemic agent for both adults and children at high risk for TLS and for this reason should be considered the uricolytic agent of choice in these patients.     

Single-dose rasburicase for tumour lysis syndrome in adults: weight-based approach

Background: The optimal rasburicase dose for adult patients has not been determined. Objective: To retrospectively examine use of rasburicase in our centre and to evaluate the effect of a single dose of rasburicase on urate and serum creatinine levels in our adult patients. Method: A retrospective chart review was conducted of all adult patients who received rasburicase for treatment of tumour lysis syndrome‐associated hyperuricaemia at our academic, urban medical centre from July 2002 to October 2006. Result: Twenty‐one patients received rasburicase with an average first dose of 0·15 ± 0·03 mg/kg. The drug dosing was calculated based on the patients’ ideal body weight (IBW) or adjusted body weight (aBW) for those who were more than 30% above their IBW. Patients experienced a mean serum urate reduction of 89·7 ± 9·0% from the baseline through the first 24 h after a single rasburicase dose (11·4 ± 4·5 mg/dL vs. 1·4 ± 1·4 mg/dL, respectively, P < 0·001). The urate levels remained within normal limits (<8 mg/dL) in all the patients for 48 h after a single dose of rasburicase. The major limitation of our study is that in 18 of 21 patients we lacked adequate documentation to ascertain that the blood samples sent for urate analysis after drug administration were handled according to the manufacturer’s recommendations. However, in this small group of patients, we observed that the effect of rasburicase on serum urate was similar to the total study population. The effect was sustained for 48 h after a single dose. Serum creatinine levels at 24–72 h after the single rasburicase dose were not significantly different from baseline (1·8 mg/dL vs. 2·3 mg/dL, respectively, P = 0·14). Conclusion: Rasburicase is an effective treatment for patients with hyperuricaemia and may aid in the prevention of hyperuricaemia‐associated nephrotoxicity. From our experience, a single dose of 0·15 mg/kg (IBW or aBW) of rasburicase appears to effectively decrease and maintain urate levels within normal limits for 48 h.     

Rasburicase for the management of tumor lysis syndrome in neonates

OBJECTIVE: To describe the management of tumor lysis syndrome (TLS) with rasburicase in 2 patients who presented with cancer within the first month of life and compare and contrast both cases with respect to their underlying renal physiology, management, and eventual outcome. CASE SUMMARY: TLS developed in 2 neonates born at 38 weeks' gestational age; both were managed in part with rasburicase. One patient was a 21-day-old infant who received 2 days of induction chemotherapy for the treatment of congenital Stage IV-S neuroblastoma. With a single 0.2 mg/kg dose of rasburicase, the serum urate level normalized and the infant completed therapy without incident. The second patient was a 4-day-old neonate with congenital precursor-B cell acute lymphoblastic leukemia who presented with spontaneous TLS complicated by renal dysfunction. Despite several doses of intravenous rasburicase (2 doses of 0.1 mg/kg and 4 doses of 0.2 mg/kg), as well as aggressive supportive therapy, the infant died of complications arising from uncontrolled TLS. DISCUSSION: Neonates may be at particular risk for TLS given their immature renal function and its predisposition toward metabolic derangements. While rasburicase has the potential to provide a rapid reversal of TLS in this patient population, when TLS is complicated by pre-existing acute renal failure, additional interventions and alternative anti-tumor strategies may be necessary for a successful outcome. When managing TLS in infancy, clinicians must consider the relative degree of renal immaturity and its predisposition toward metabolic derangements. CONCLUSIONS: Rasburicase appears to be well tolerated and effective in lowering serum urate concentrations in the treatment of therapy-related TLS in neonates. However, in instances of spontaneous TLS complicated by the normally low glomerular filtration rate in the newborn infant, the use of rasburicase and other supportive care measures may still be inadequate, warranting further study.     

Treatment of impending tumor lysis with single-dose rasburicase

OBJECTIVE: To report the experience of using rasburicase as a single-dose treatment for childhood leukemia presenting with hyperuricemia. CASE SUMMARIES: Three children with acute lymphoblastic leukemia presenting with hyperuricemia received rasburicase as a single intravenous dose just prior to the start of chemotherapy. This was followed by rapid reduction of serum uric acid levels within 24 hours, which remained low throughout induction therapy while allopurinol and hydration therapy without urinary alkalinization ensued. Subclinical tumor lysis was evidenced by the appearance of hyperphosphatemia and hypocalcemia in all cases and hyperkalemia in 1 patient. These abnormalities were transient, and each patient's renal function gradually improved from pretreatment baseline without requiring dialysis. DISCUSSION: Our experience suggests that hyperuricemia in children at risk for tumor lysis can be managed with a briefer regimen of rasburicase than the recommended 5- to 7-day course. CONCLUSIONS: A shorter course of rasburicase treatment, including single-dose injection, is feasible and will improve the cost-effectiveness profile of the otherwise expensive compound.     

Rasburicase for the treatment and prevention of hyperuricemia

OBJECTIVE: To review the information currently available on rasburicase for treatment and prevention of hyperuricemia. DATA SOURCES: MEDLINE (1966-August 2002) was searched for primary and review articles. STUDY SELECTION/DATA EXTRACTION: Studies evaluating rasburicase, including abstracts and proceedings, were considered for inclusion. English-language literature was evaluated for the pharmacology, pharmacodynamics, pharmacokinetics, therapeutic use, and adverse effects of rasburicase. DATA SYNTHESIS: Rasburicase, a recombinant urate oxidase, has been shown to be effective in lowering uric acid and preventing uric acid accumulation in patients with hematologic malignancies who had hyperuricemia or who were at high risk for developing hyperuricemia. It has been approved for pediatric use in the US. CONCLUSIONS: In addition to allopurinol, hydration, and urinary alkalinization, rasburicase is a new alternative for the treatment and prevention of hyperuricemia in patients with hematologic malignancies. Its rapid onset of action and the ability to lower preexisting elevated uric acid levels are the advantages of rasburicase compared with allopurinol. It may allow the patient to receive chemotherapy treatment without delay.     

Theophylline disposition in obesity

Theophylline disposition was examined in 14 obese subjects and 57 normal subjects. A single oral dose of aminophylline solution was given and serum and saliva samples were collected over several hours and assayed by high-pressure liquid chromatography. The apparent volume of distribution (Vd) and body clearance (ClB) were analyzed for total body weight (TBW) and ideal body weight (IBW). The Vd averaged 0.482 (SD = 0.084) L/kg TBW in normals vs 0.382 (0.069) L/kg TBW and 0.77 (0.189) L/kg IBW in obese subjects. The ClB averaged 63.0 (28.5) ml/hr/kg IBW in normals compared to 32.8 (11.1) ml/hr/kg TBW and 64.1 (20.8) ml/hr/kg IBW in obese subjects. Similar Vd values between the two groups when TBW is used indicates that loading dose is best calculated based on TBW. Similar ClB based on IBW in normal and obese subjects indicates that IBW should be used to calculate maintenance doses for theophylline. Mean half-lives were longer in obese subjects than in normals, 8.6 (2.0) and 6.0 (2.1) hr, respectively, suggesting that obese patients may need less frequent dosing.     

Hemolysis and methemoglobinemia secondary to rasburicase administration

OBJECTIVE: To report a case of hemolytic anemia and methemoglobinemia developing after rasburicase administration to a patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency. CASE SUMMARY: A 50-year-old African American man was hospitalized with new onset seizure, diabetic ketoacidosis, respiratory failure, and acute renal failure. Serum uric acid concentrations were elevated, and the patient was treated with one dose of intravenous rasburicase 22.5 mg for acute renal failure secondary to hyperuricemia. Routine arterial blood gas analyses performed after rasburicase was administered revealed elevated methemoglobin concentrations, which peaked at 14.7%. Hemolytic anemia developed as evidenced by a fall in blood hemoglobin from 14.8 to 5.3 g/dL. The patient made a full recovery following aggressive fluid therapy, blood transfusions, and respiratory support. G6PD deficiency was subsequently confirmed. The Naranjo probability scale indicated that rasburicase was a probable cause of hemolytic anemia and methemoglobinemia. DISCUSSION: Rasburicase is contraindicated in patients with G6PD deficiency as it may cause hemolytic anemia and methemoglobinemia. As of September 26, 2005, simultaneous occurrence of hemolytic anemia and methemoglobinemia has not been reported in patients receiving rasburicase. CONCLUSIONS: As of September 26, 2005, screening for G6PD deficiency should be performed whenever possible prior to chemotherapy administration in patients at risk of developing tumor lysis syndrome.     

Prospective,Controlled Study of Acyclovir Pharmacokinetics in Obese Patients

The current recommendations for intravenous (i.v.) acyclovir dosing in obese patients suggest using ideal body weight (IBW) rather than total body weight (TBW). To our knowledge, no pharmacokinetic analysis has validated this recommendation. This single-dose pharmacokinetic study was conducted in an inpatient oncology population. Enrollment was conducted by 1:1 matching of obese patients (>190% of IBW) to normal-weight patients (80 to 120% of IBW). All patients received a single dose of i.v. acyclovir, 5 mg/kg, infused over 60 min. Consistent with current recommendations, IBW was used for obese patients and TBW for normal-weight patients. Serial plasma concentrations were obtained and compared. Seven obese and seven normal-weight patients were enrolled, with mean body mass indexes of 45.0 and 22.5 kg/m², respectively. Systemic clearance was substantially higher in the obese than normal-weight patients (mean, 19.4 ± 5.3 versus 14.3 ± 5.4 liters/h; P = 0.047). Area under the concentration-time curve was lower in the obese patients (15.2 ± 2.9 versus 24.0 ± 9.4 mg · h/liter; P = 0.011), as was maximum concentration (5.8 ± 0.9 versus 8.2 ± 1.3 mg/liter; P = 0.031). Utilization of IBW for dose calculation of i.v. acyclovir in obese patients leads to lower systemic exposure than dosing by TBW in normal-weight patients. While not directly evaluated in this study, utilization of an adjusted body weight for dose determination appears to more closely approximate the exposure seen in normal-weight patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01714180.)     

Rasburicase (Fasturtec)

Rasburicase (Fasturtec) is an enzyme that transforms uric acid to the more water soluble allantoin to be excreted by the kidneys. Rasburicase fulfills an unmet clinical need in the treatment of hyperuricemia in that it produces a more rapid action of controlling serum uric acid compared with allopurinol. Tumours with high proliferative rate and sensitive to chemotherapy such as hematological malignancies (mainly) solid tumours (occasionally) may lead to a tumor lysis syndrome. In this situation rasburicase can effectively lower serum uric acid concentrations with a secondary improvement in renal function. Hyperuricemia is the hallmark of severe gout with tophi formation. Rasburicase represents an interesting new option in controlling serum uric acid in patients with severe tophaceous gout.     

Crystal arthropathies: recognizing and treating "the gouch"

Gout is a common disease and the prevalence is increasing. Chronic hyperuricemia (uric acid serum levels >6.8 mg/dL) is a key feature. Treating to a target uric acid level of 6.0 mg/dL is recommended. In addition to cochicine, probenecid, and allopurinol, feboxostat is a new option for urate-lowering therapy.     

Hyperxanthinemia interferes with serum uric acid determinations by the uricase method.

Serum xanthine concentrations as high as 148 mg/L were noted after treatment of a patient with Burkitt's lymphoma who was receiving allopurinol. These markedly above-normal values for xanthine led to spuriously low values for serum uric acid as measured by the uricase method. Rapid tumor lysis in patients who are receiving allopurinol may lead to marked hyperxanthinemia, which in turn may obscure hyperuricemia in such patients when the uricase method is used for uric acid analysis. In such situations, uric acid concentrations should be measured by the phosphotungstate colorimetric assay.     

Influence of morbid obesity on the single-dose pharmacokinetics of daptomycin

The present study characterized the single-dose pharmacokinetics of daptomycin dosed as 4 mg/kg of total body weight (TBW) in seven morbidly obese and seven age-, sex-, race-, and serum creatinine-matched healthy subjects. The glomerular filtration rate (GFR) was measured for both groups following a single bolus injection of [(125)I]sodium iothalamate. Noncompartmental analysis was used to determine the pharmacokinetic parameters, and these values were normalized against TBW, ideal body weight (IBW), and fat-free weight (FFW) for comparison of the two groups. All subjects enrolled in this study were female, and the mean (+/-standard deviation) body mass index was 46.2 +/- 5.5 kg/m(2) or 21.8 +/- 1.9 kg/m(2) for the morbidly obese or normal-weight group, respectively. The maximum plasma concentration and area under the concentration-time curve from dosing to 24 h were approximately 60% higher (P < 0.05) in the morbidly obese group than in the normal-weight group, and these were a function of the higher total dose received in the morbidly obese group. No differences in daptomycin volume of distribution (V), total clearance, renal clearance, or protein binding were noted between the two groups. Of TBW, FFW, or IBW, TBW provided the best correlation to V. In contrast, TBW overestimated GFR through creatinine clearance calculations using the Cockcroft-Gault equation. Use of IBW in the Cockcroft-Gault equation or use of the four-variable modification of diet in renal disease equation best estimated GFR in morbidly obese subjects. Further studies of daptomycin pharmacokinetics in morbidly obese patients with acute bacterial infections and impaired renal function are necessary to better predict appropriate dosage intervals.     

饮食核酸对SPF级家鸡血尿酸水平的影响

目的探讨饮食核酸对 SPF级家鸡血尿酸水平的影响. 方法选 30日龄 SPF级家鸡按血尿酸水平随机分成急性、亚急性和亚慢性研究 3组,各组再按血尿酸水平随机分成 5个亚组,在常规饲料基础上,分别饲以添加不同剂量酵母 RNA的饮食.动态监测血尿酸水平;分期脱颈椎处死实验动物,测定胸腺、法氏囊和肝脏、脾脏的脏器指数,并进行病理学观察. 结果各添加酵母 RNA实验组动物的体质量、脏器指数和病理组织学观察与 0剂量添加组相比均无统计学差异( P >0.05);饮食中添加酵母 RNA引起 SPF家鸡血尿酸水平升高至 0.41 mmol/L的急性作用阈剂量和亚急性作用阈剂量为 6.0 g/(kg· d),相当于成人日推荐补充量的 180倍;其亚慢性作用阈剂量为 8.0 g/(kg· d),相当于成人日推荐补充量的 240倍. 结论饮食核酸可影响血尿酸水平;成人日补充量 2 g/d是安全的,不会引起血尿酸水平的异常持续性升高而产生高尿酸血症和痛风.     

Tobramycin pharmacokinetics in morbidly obese patients.

Tobramycin kinetics were examined in 9 morbidly obese women following a single intravenous (120 mg) bolus. After the injection, serum elimination conformed to a 2-compartment open model with alpha and beta t1/2s of 0.285 and 2.1 hr. The volume of distribution (Varea) was determined to be 0.44 1/kg ideal body weight (IBW) and 0.20 1/kg total body weight (TBW). To normalize Varea to 0.26 1/kg, 58% of the patients' adipose weight (TBW -- IBW) must also be taken into account.     

Preservation of Renal Function during Gout Treatment with Febuxostat: A Quantitative Study

Abstract

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.     

Tumor lysis syndrome: pathophysiology, definition, and alternative treatment approaches

Tumor lysis syndrome (TLS), a life threatening metabolic syndrome seen in malignancies with high tumor burden, is reviewed in this article. The new Cairo and Bishop classification system is discussed as well as the clinical management of this syndrome. Special emphasis is placed on the use of a relatively new agent, rasburicase, as an alternative to allopurinol in the management of TLS-associated hyperuricemia.     

Laparoscopic Roux-en-Y gastric bypass in a morbidly obese patient with renal transplant: a case report

Renal transplant is the only curative treatment for end-stage renal disease. As diabetes and obesity are the major causes of graft failure and post-transplant complication, it is important to manage obesity in patients with renal transplant. Herein, we report a case of a morbidly obese renal-transplant patient with poorly controlled diabetes who received bariatric surgery. A 34-year-old obese Taiwanese man with type 2 diabetes had end-stage renal disease that had progressed since 2008, when he had commenced hemodialysis (January 2008) and had a renal transplant (July 2008). Because of persistent obesity and poorly controlled diabetes, he received LRYGB at Chiayi Christian hospital on 18 August 2010. In the month that followed, he lost 10 kg. His serum creatinine decreased to 1.11 mg/dL (1.4 mg/dL, preoperative) and his hemoglobin A1c decreased to 8.5% (10.4%, preoperative). These results indicate that, in obese renal transplant patients, LRYGB may be employed to treat obesity, control diabetes and stabilize or improve the renal function.     

Drugs to lower uric acid levels. How to avoid misuse in gouty arthritis

Several points regarding the use of drugs to lower uric acid levels deserve emphasis. First, these agents are not useful in the management of acute gout. Second, all forms of the drugs should be initiated at low dose with gradual increments to achieve a serum uric acid level between 5 and 6 mg/dL. There are no data to support the widely presumed notion that dropping the uric acid level to a very low range (1 to 3 mg/dL) hastens resorption of tophi or improves joint function. Third, the uricosuric agents probenecid (Benemid) and sulfinpyrazone (Anturane) interact with a number of drugs, and both the patient and physician should be aware of this. Finally, and most important, careful and frequent monitoring is needed during the first several months of therapy with these drugs.     

降尿酸治疗对脑梗死患者血管内皮功能的影响

目的:研究高尿酸血症的急性脑梗死患者降尿酸治疗对血管内皮功能及血压的影响。方法:搜集同一中心共138例患者入选该研究。高尿酸血症并急性脑梗死者入选92例,随机（随机数字法）分为实验组46例,对照组46例,同时入选同期血尿酸正常的急性脑梗死患者46例,实验组口服别嘌醇3个月治疗高尿酸血症。对这些人群进行抽血化验,记录治疗前后血尿酸、血脂及hs-CRP,同时检测患者血压、体质量指数（BMI）,并采用超声无创血流介导的血管舒张功能（FMD）进行血管内皮功能评估,治疗前后各组之间比较并进行统计学分析。结果:别嘌醇治疗3个月后实验组血尿酸[(479.7±49.0) μmol/L vs. (381.2±76.7)μmol/L]、hs-CRP[(8.1±6.7) mg/L vs. (5.1±4.6) mg/L]、收缩压[(124.7±26.3) mmHg vs. (97.4±13.5) mmHg]明显降低( P<0.05),FMD[(7.6±3.5%) vs. (11.2±3.9%)]明显升高( P<0.05),FMD升高的程度与血尿酸降低的程度呈正相关( r=0.463, P<0.01),多元回归分析显示血尿酸是FMD的独立影响因子（ β=-0.229, P=0.035)。 结论:高尿酸血症的急性脑梗死患者中降尿酸治疗可明显改善患者的血管内皮功能,改善炎症状态,降低患者血压,进一步印证了高尿酸血症导致血管内皮功能紊乱,促进动脉粥样硬化的发生与发展。