A long-term,open-label extension study on the safety of treatment with lanthanum carbonate,a new phosphate binder,in patients receiving hemodialysis

ABSTRACT

Background: Lanthanum carbonate, a new phosphate binder, is effective in reducing serum phosphorus levels in patients with end-stage renal disease. A 1-year extension study to two randomized controlled studies was conducted to evaluate the long-term safety of lanthanum carbonate in patients who received hemodialysis.

Research design and methods: Patients from two previous lanthanum carbonate studies were eligible to continue treatment in a 1-year open-label extension. A total of 77 patients (N = 77; 11 from Study 1, 66 from Study 2) were enrolled in this extension. The mean age of patients was 60.9 years (SD ± 12.5 years); 65% were male and 35% were female. All patients received lanthanum carbonate at the optimal dose for phosphorus control, determined in their previous study. Safety and tolerability were assessed by monitoring adverse events, laboratory parameters, and vital signs. The number of patients who maintained serum phosphorus levels at ≤ 5.9?mg/dL (1.9?mmol/L) was recorded, along with serum calcium, calcium × phosphorus product, and parathyroid hormone levels.

Results: Lanthanum carbonate was well tolerated and was associated with few treatment-related adverse events. The most commonly reported adverse events were nausea (26.0%), peripheral edema (23.4%), and myalgia (20.8%). No treatment-related serious adverse events occurred. By Week 4, the mean serum phosphorus level had decreased by approximately 1?mg/dL to 5.7 ± 2.0?mg/dL (1.84 ± 0.7?mmol/L). At the end of the study, the mean pre-dialysis serum phosphorus level was 5.7 ± 1.4?mg/dL (1.84 ± 0.5?mmol/L); 53% of patients had controlled phosphorus levels. Calcium × phosphorus product decreased during Week 1 and remained within a clinically acceptable range thereafter. There were no clinically significant changes in serum calcium, or parathyroid hormone levels.

Conclusion: Lanthanum carbonate is well tolerated and is effective for the long-term maintenance of serum phosphorus control in patients with end-stage renal disease.     

A long-term, open-label extension study on the safety of treatment with lanthanum carbonate, a new phosphate binder, in patients receiving hemodialysis

BACKGROUND: Lanthanum carbonate, a new phosphate binder, is effective in reducing serum phosphorus levels in patients with end-stage renal disease. A 1-year extension study to two randomized controlled studies was conducted to evaluate the long-term safety of lanthanum carbonate in patients who received hemodialysis. RESEARCH DESIGN AND METHODS: Patients from two previous lanthanum carbonate studies were eligible to continue treatment in a 1-year open-label extension. A total of 77 patients (N = 77; 11 from Study 1, 66 from Study 2) were enrolled in this extension. The mean age of patients was 60.9 years (SD +/- 12.5 years); 65% were male and 35% were female. All patients received lanthanum carbonate at the optimal dose for phosphorus control, determined in their previous study. Safety and tolerability were assessed by monitoring adverse events, laboratory parameters, and vital signs. The number of patients who maintained serum phosphorus levels at < or = 5.9 mg/dL (1.9 mmol/L) was recorded, along with serum calcium, calcium x phosphorus product, and parathyroid hormone levels. RESULTS: Lanthanum carbonate was well tolerated and was associated with few treatment-related adverse events. The most commonly reported adverse events were nausea (26.0%), peripheral edema (23.4%), and myalgia (20.8%). No treatment-related serious adverse events occurred. By Week 4, the mean serum phosphorus level had decreased by approximately 1 mg/dL to 5.7 +/- 2.0 mg/dL (1.84 +/- 0.7 mmol/L). At the end of the study, the mean pre-dialysis serum phosphorus level was 5.7 +/- 1.4 mg/dL (1.84 +/- 0.5 mmol/L); 53% of patients had controlled phosphorus levels. Calcium x phosphorus product decreased during Week 1 and remained within a clinically acceptable range thereafter. There were no clinically significant changes in serum calcium, or parathyroid hormone levels. CONCLUSION: Lanthanum carbonate is well tolerated and is effective for the long-term maintenance of serum phosphorus control in patients with end-stage renal disease.     

Relative in vitro efficacy of the phosphate binders lanthanum carbonate and sevelamer hydrochloride

The high tablet burden and poor compliance associated with phosphate-binding drugs has led to a search for more potent agents. In vitro-binding studies were performed on the recently introduced binder, lanthanum carbonate (LC; Fosrenol), to compare its phosphate-binding affinity with sevelamer hydrochloride (SH; Renagel). Langmuir equilibrium binding affinities (K(1)) for LC and SH were established using different phosphorus (5-100 mM) and binder (134-670 mg per 50 mL) concentrations at pH 3-7, with or without salts of bile acids present (30 mM). At all pH levels, LC had a higher binding affinity for phosphate than SH. For LC, K(1) was 6.1 +/- 1.0 mM(-1) and was independent of pH. For SH, K(1) was pH dependent, being 1.5 +/- 0.8 mM(-1) at pH 5-7 and 0.025 +/- 0.002 mM(-1) at pH 3, that is, >200 times lower than for LC. In the presence of 30 mM bile salts, SH lost 50% of its phosphate, whereas no displacement of phosphate occurred for LC. These findings indicate that LC binds phosphate more effectively than SH across the pH range encountered in the gastrointestinal tract, and has a lower propensity for bound phosphate to be displaced by competing anions in the intestine.     

碳酸镧咀嚼片体外磷结合试验的一般考虑

碳酸镧咀嚼片于2004年由美国FDA批准上市,作为一种磷结合剂用于降低终末期肾病患者血清磷酸盐.碳酸镧是胃肠道(GI)局部作用药物,口服吸收率非常低,不适合采用常规的体内药动学(PK)终点方法评价生物等效性.FDA认为,体外溶出试验和磷酸盐结合研究可用于证明碳酸镧生物等效性.本文在FDA个药指南和文献资料基础上,从方法...     

Calcium carbonate as a phosphate binder in children on continuous ambulatory peritoneal dialysis and hemodialysis.

The aim of the study was the evaluation of the efficacy of calcium carbonate (CaCO3) in the control of serum phosphorus level in children with ESRD. Sixteen patients (group I) were evaluated retrospectively, 25 pts (group II) were observed prospectively. The pts from group I were treated with CaCO3 (100-800 mg/kg/day) with or without Al(OH)3 and with different doses of DHT. The pts from group II were treated with CaCO3 and DHT without Al(OH)3 but some of them had obtained Al(OH)3 in the past. The doses of CaCO3 were individually adjusted to maintain the serum calcium level 5.0-5.5 mEq/l. In the pts on CAPD evaluated retrospectively the control of serum phosphorus level was better and episodes of hypercalcemia were more frequent than in the pts on HD. Neither the concomitant use of Al(OH)3 with CaCO3 nor varying the dosage of DHT within assumed range influenced serum phosphorus level. The differences in serum phosphorus level and in the frequency of episodes of hypercalcemia in pts in group II were less obvious then in group I. It may depend on more precise adjustment of CaCO3 doses to the individual needs of these pts. The episodes of hypercalcemia in the group II were more frequent in pts who received Al(OH)3 in the past.     

Absolute bioavailability and disposition of lanthanum in healthy human subjects administered lanthanum carbonate

Lanthanum carbonate [La2(CO3)3] is a noncalcium, non-aluminum phosphate binder indicated for hyperphosphatemia treatment in end-stage renal disease. A randomized, open-label, parallel-group, phase I study was conducted to determine absolute bioavailability and investigate excretory routes for systemic lanthanum in healthy subjects. Twenty-four male subjects were randomized to a single lanthanum chloride (LaCl3) intravenous infusion (120 microg elemental lanthanum over a 4-hour period), a single 1-g oral dose [chewable La2(CO3)3 tablets; 4 x 250 mg elemental lanthanum], or no treatment (control). Serial blood, urine, and fecal samples were collected for 7 days postdosing. The absolute bioavailability of lanthanum [administered as La2(CO3)3] was extremely low (0.00127% +/- 0.00080%), with individual values in the range of 0.00015% to 0.00224%. Renal clearance was negligible following oral administration (1.36 +/- 1.43 mL/min). Intravenous administration confirmed low renal clearance (0.95 +/- 0.60 mL/min), just 1.7% of total plasma clearance. Fecal lanthanum excretion was not quantifiable after intravenous administration owing to high and variable background fecal lanthanum and constraints on the size of the intravenous dose. These findings demonstrate that lanthanum absorption from the intestinal tract into the systemic circulation is extremely low and that absorbed drug is cleared predominantly by nonrenal mechanisms.     

A comparative review of the efficacy and safety of established phosphate binders: calcium,sevelamer, and lanthanum carbonate*

ABSTRACT

Background: Obstacles to successful management of hyperphosphatemia in chronic kidney disease include inadequate control of dietary phosphate and non-compliance with phosphate-binder therapy. Three major classes of phosphate binders include calcium-based binders, sevelamer HCl, and lanthanum carbonate.

Scope: A literature search was performed using MEDLINE and EMBASE databases to identify clinical trials from January 1966 to May 2007 comparing classes of phosphate binders with regard to efficacy, safety, compliance, or pharmacoeconomics. Search terms included lanthanum AND sevelamer, lanthanum AND calcium, and sevelamer AND calcium. A total of 1372 articles were identified in the search, with 125 review articles and clinical trials of interest identified.

Findings: Calcium-based binders are effective, but their potential to contribute to total body calcium overload and vascular calcification is an important long-term clinical concern. Sevelamer HCl is effective in reducing serum phosphate, has no systemic absorption, and does not increase total body calcium load. However, sevelamer HCl binds bile acids, is not an efficient phosphate binder in an acidic environment, and contributes to metabolic acidosis. Lanthanum carbonate is a potent and selective phosphate binder that retains high affinity for phosphate over a wide pH range, does not bind bile acids or contribute to metabolic acidosis, and has the potential to reduce pill burden and increase patient compliance compared with other phosphate binders.

Conclusions: All three classes of phosphate binders are effective at reducing serum phosphate levels. Lanthanum carbonate may result in increased adherence by decreasing the pill burden.     

马尔可夫模型评价三种磷结合剂治疗高磷血症的研究

目的：评价碳酸钙、碳酸镧和盐酸司维拉姆三者在治疗高磷血症方面的经济性。方法：通过构建马尔可夫模型进行成本效果评价。结果：碳酸镧降磷效果最好,盐酸司维拉姆次之,碳酸钙最差,但考虑成本之后碳酸钙为最优方案。结论：在3倍人均GDP为支付阈值的条件下碳酸钙是最具有成本效果优势的方案。     

Pharmacodynamics and pharmacokinetics of disopyramide phosphate

Based on pharmacodynamic and pharmacokinetic studies in 42 patients with paroxysmal and extrasystolic abnormalities of the rhythm it was established that disopyramide phosphate (ritmilen) is an effective antiarrhythmic agent for atrial fibrillation paroxysms. The drug exerts negative, chronotropic, dromotropic and inotropic effects, especially upon intravenous injections for removal of atrial fibrillatin paroxysms. Ritmilen moderately reduces the blood pressure. When used for removal of atrial fibrillation paroxysms ritmilen is effective in doses of 1.2-1.7 mg/kg intravenously and in doses of 2.5-3.8 mg/kg per os. In patients with chronic ventricular premature heart beat the single effective drug doses amount to 0.61-1.7 mg/kg. After oral use the ritmilen concentration in blood plasma is lower than after intravenous use in adequate doses. No relationship has been found between the drug antiarrhythmic effect and blood plasma concentration.     

Clinical pharmacokinetics of the retinoids

Etretinate, isotretinoin (13-cis-retinoic acid), and tretinoin (all-trans-retinoic acid) are retinoic acid analogues comprising a group of compounds known as the retinoids. However, they exhibit distinct and important differences with regard to their therapeutic and toxicological profiles. Tretinoin, due to a low oral therapeutic index, is limited almost exclusively to topical application, whereas etretinate and isotretinoin are therapeutically effective when given systemically by the oral route. Clinical doses of isotretinoin range from 0.5 to 8 mg/kg/day, with acute side effects appearing following doses of 1 mg/kg/day or greater. Plasma concentrations of isotretinoin following single and multiple doses peak between 2 to 4 hours and exhibit elimination half-lives of 10 to 20 hours. Isotretinoin blood concentration-time curves following a single- or multiple-dose regimen are well described by a linear model with biphasic disposition characteristics. Etretinate, which possesses a narrower therapeutic concentration range than isotretinoin, is used clinically at doses between 0.5 to 1.5 mg/kg/day; acute side effects appear following doses of 0.5 mg/kg/day or more. In most conditions, the retinoids produce a maximal effect in about 8 weeks (at the highest tolerated dose), with a slow recurrence of symptoms usually occurring within several weeks following cessation of treatment - except in the treatment of cystic acne with isotretinoin. Maintenance or intermittent dosing usually results in a prolongation of remission. Pharmacokinetically, the major difference between isotretinoin and etretinate is the much longer elimination half-life (120 days) of etretinate following long term administration. Recently, however, blood concentration versus time curves from day 1 to day 180 of etretinate therapy have been fitted by a single polyexponential pharmacokinetic equation without the need to invoke non-linearity in the kinetics. The observed lengthening of the elimination half-life with multiple dosing may thus be due to a lack of assay sensitivity at drug concentrations seen after single-dose administration, rather than to time-related alterations in the pharmacokinetics of etretinate.     

Clinical pharmacokinetics of the salicylates

The use of salicylates in rheumatic diseases has been established for over 100 years. The more recent recognition of their modification of platelet and endothelial cell function has lead to their use in other areas of medicine. Aspirin (acetylsalicylic acid) is still the most commonly used salicylate. After oral administration as an aqueous solution aspirin is rapidly absorbed at the low pH of the stomach millieu. Less rapid absorption is observed with other formulations due to the rate limiting step of tablet disintegration - this latter factor being maximal in alkaline pH. The rate of aspirin absorption is dependent not only on the formulation but also on the rate of gastric emptying. Aspirin absorption follows first-order kinetics with an absorption half-life ranging from 5 to 16 minutes. Hydrolysis of aspirin to salicylic acid by nonspecific esterases occurs in the liver and, to a lesser extent, the stomach so that only 68% of the dose reaches the systemic circulation as aspirin. Both aspirin and salicylic acid are bound to serum albumin (aspirin being capable of irreversibly acetylating many proteins), and both are distributed in the synovial cavity, central nervous system, and saliva. The serum half-life of aspirin is approximately 20 minutes. The fall in aspirin concentration is associated with a rapid rise in salicylic acid concentration. Salicylic acid is renally excreted in part unchanged and the rate of elimination is influenced by urinary pH, the presence of organic acids, and the urinary flow rate. Metabolism of salicylic acid occurs through glucuronide formation (to produce salicyluric acid), and salicyl phenolic glucoronide), conjugation with glycine (to produce salicyluric acid), and oxidation to gentisic acid. The rate of formation of salicyl phenolic glucuronide and salicyluric acid are easily saturated at low salicylic acid concentrations and their formation is described by Michaelis-Menten kinetics. The other metabolic products follow first-order kinetics. The serum half-life of salicylic acid is dose-dependent; thus, the larger the dose employed, the longer it will take to reach steady-state. There is also evidence that enzyme induction of salicyluric acid formation occurs. No significant differences exist between the pharmacokinetics of the salicylates in the elderly or in children when compared with young adults. Apart from differences in free versus albumin-bound salicylate in various disease states and physiological conditions associated with low serum albumin, pharmacokinetic parameters in patients with rheumatoid arthritis, osteoarthritis, chronic renal failure or liver disease are essentially the same.(ABSTRACT TRUNCATED AT 400 WORDS)     

Steady-state pharmacokinetics of lithium carbonate in healthy subjects.

1. The pharmacokinetics of lithium in six healthy volunteers stabilised on lithium were investigated and appropriate pharmacokinetic parameters calculated. 2. The results illustrate important differences in single and multiple dose lithium pharmacokinetics; the implications for minimising lithium-induced renal damage are discussed.     

碳酸镧对维持性血液透析患者并继发性甲旁亢的高血磷影响

目的观察碳酸镧对维持性血液透析患者并继发性甲旁亢的高磷血症的影响。方法将31例血清全段甲状旁腺素（iFFH〉300-500pg/ml的维持性血液透析患者随机分为2组,每组均口服骨化三醇1．0ug,2次／周冲击治疗。观察组给予口服碳酸镧咀嚼片（Fosren01）500mg,3次／d,14例。对照组给予醋酸钙片667mg,3次／d,17例。结果治疗8周后观察组血磷及iFFH较治疗前明显下降,血磷较对照组有明显下降,差异有统计学意义（P〈0．05）。结论碳酸镧可有效降低MHD患者并继发性甲旁亢用骨化三醇冲击治疗时的血磷水平。     

Population pharmacokinetics of fingolimod phosphate in healthy participants

Fingolimod (FTY720) is a sphingosine 1-phosphate receptor (S1PR) modulator currently being evaluated for the treatment of multiple sclerosis. Fingolimod undergoes phosphorylation in vivo to yield fingolimod phosphate (fingolimod-P), which modulates S1PRs expressed on lymphocytes and cells in the central nervous system. The authors developed a population model, using pooled data from 7 phase 1 studies, to enable characterization of fingolimod-P pharmacokinetics following oral administration of fingolimod and to evaluate the impact of key demographic variables on exposure. The fingolimod-P concentration-time course after either single or multiple doses of fingolimod was described by a 2-compartment model with first-order apparent formation and elimination, lag time in the apparent formation, and dose-dependent relative bioavailability and apparent central volume of distribution. Body weight and ethnicity were identified as demographic covariates correlated with the disposition of fingolimod-P. Model predictions indicated no need for dose adjustment of fingolimod based on body weight; the effect of ethnicity on the disposition of fingolimod requires further investigation. The accurate prediction of the pharmacokinetic profile of fingolimod-P determined empirically in 2 large phase 3 trials provides external validation of the model.     

Clinical pharmacokinetics of the newer benzodiazepines

New benzodiazepine derivatives continue to be developed and introduced into clinical use. The pharmacokinetic properties of these newer drugs can best be understood by their categorisation according to range of elimination half-life and pathway of metabolism (oxidation versus conjugation). Clobazam and halazepam are long half-life (and therefore accumulating) anxiolytics metabolised by oxidation. Alprazolam and clotiazepam also are oxidised compounds but have short to intermediate half-life values and therefore produce considerably less accumulation. Temazepam and lormetazepam are hypnotic agents with intermediate half-lives but metabolised by conjugation. The most unique of the newer benzodiazepines are the ultra-short half-life (oxidised) compounds midazolam, triazolam and brotizolam, which are essentially non-accumulating during multiple dosage.     

碳酸镧治疗维持性血液透析患者高磷血症的短期疗效及安全性

目的观察碳酸镧治疗维持性血液透析患者高磷血症的短期疗效及安全性。方法选取维持性血液透析并高磷血症患者42例,随机分为两组,每组21例。试验组给予碳酸镧咀嚼片,根据患者的血磷值制定碳酸镧的使用剂量;对照组给予碳酸钙D_3咀嚼片,1片,bid;治疗周期均为12周。观察两组血磷、血钙、钙磷乘积、血全段甲状旁腺素水平变化及不良反应。结果试验组和对照组血磷分别于治疗2周和4周后出现下降,试验组血磷下降幅度大于对照组(P<0.05)。试验组治疗前后血钙水平无明显变化(均P>0.05),对照组治疗后血钙升高(P<0.05)。试验组钙磷乘积下降,且低于同时点对照组,差异显著(P<0.05)。试验组和对照组胃肠道反应发生率分别为29%和24%(P>0.05),高钙血症发生率分别为0和29%(P<0.05)。结论与碳酸钙相比,碳酸镧具有更快、更好的降血磷效果,且不会导致高钙血症,是治疗维持性血液透析患者高磷血症安全有效的药物。     

高品质碳酸镧晶簇的合成与表征

目的：合成高品质的碳酸镧晶簇,并对合成的样品进行表征。方法采用碳酸氢钠与氯化镧反应,通过控制体系 pH 值,并添加一定量的乙醇,合成了高品质的碳酸镧。采用 X 射线衍射、傅里叶红外光谱、扫描电镜以及热重分析等分析方法对合成的样品进行了表征。结果结果表明,通过添加乙醇可以得到层状的碳酸镧晶簇,其晶簇尺寸约为20～50μm,层厚为0．6～0．8μm。结论碳酸镧较高的比表面积更有利于与磷结合,进而降低胃肠道对磷的吸收。     

碳酸镧对维持性血液透析患者高磷血症的疗效及安全性

目的探讨碳酸镧对维持性血液透析患者高磷血症治疗的有效性和安全性。方法采用多中心、队列研究方式,选择符合纳入标准的维持性血透患者60例,将其分为2组,每组30例,分别使用碳酸镧或醋酸钙进行降磷治疗,观察时间为8周,定期检测各项血生化指标,记录不良反应。结果治疗前,两组透析患者血磷、血钙水平比较差异无统计学意义(P>0.05),治疗结束时,两组血磷水平均降低(P<0.05)。但治疗后2、4、8周,碳酸镧组血磷水平均低于醋酸钙组(P<0.05),血磷水平达标率(<1.78 mmol/L)高于醋酸钙组(P<0.05)。治疗结束时,碳酸镧组血钙水平与治疗前比较差异无统计学意义(P>0.05),而醋酸钙组血钙水平升高(P<0.05)。碳酸镧组的各期发生高钙血症比率及累计不良反应发生率均低于醋酸钙组(P<0.05)。结论相较于常用含钙磷结合剂醋酸钙,碳酸镧对于维持性血液透析患者具有更好的降磷效果,且高钙血症的发生率降低,可避免增加血管钙化的风险,且不增加患者的不良反应。