Shire Pharmaceutical Development Ltd, Basingstoke, United Kingdom.
Clin Ther. 2012 Jun;34(6):1290-1300.e2. doi: 10.1016/j.clinthera.2012.05.003. Epub 2012 May 31.
Phosphate binders are commonly used in tablet form to help patients with hyperphosphatemia limit their absorption of dietary phosphate. These patients frequently have a heavy tablet burden so alternative formulations provide choice and may support adherence. Lanthanum carbonate (LC) is a phosphate binder currently available as a chewable tablet. This study was conducted to support an application for marketing authorization for the oral powder formulation within the European Union.
The goal of this study was to examine the pharmacodynamics, pharmacokinetics, and tolerability of an oral powder formulation of LC compared with the reference chewable tablet formulation.
A Phase I, single-center, randomized, open-label, 2-period, crossover study to assess pharmacodynamic equivalence of the 2 formulations was conducted in healthy adults aged 18 to 55 years receiving a diet standardized for phosphate content. Individuals were randomized to receive a different formulation in each period, taking 10 doses of 1000-mg LC at 3000 mg/d per period with an intervening washout of ≥14 days. The primary pharmacodynamic variable was mean daily excretion of urinary phosphorus over 3 days while receiving LC. Pharmacodynamic equivalence was confirmed if the 90% CI for the difference between formulations in least squares (LS) mean excreted urinary phosphorus was within ±20% of the LS mean value for the tablet formulation. Secondary end points included determination of pharmacokinetic parameters and assessment of tolerability by recording of adverse events.
In total, 72 individuals entered the study. They were predominantly men (72.2%), with a mean (SD) age of 31.4 (8.26) years and a BMI of 25.8 (2.45) kg/m(2). The LS mean (SE) excreted urinary phosphorus was 16.8 (0.48) mmol/d during administration of LC tablets (±20% = ±3.35 mmol/d). The corresponding value during administration of LC oral powder was 15.2 (0.48) mmol/d; 90% CI for the difference between formulations was -2.38 to -0.82 mmol/d, confirming pharmacodynamic equivalence. The most common adverse events were gastrointestinal, and no serious adverse events were recorded.
In this multiple-dose study, the oral powder and tablet formulations of LC were well tolerated and met the regulatory criteria for pharmacodynamic equivalence in these healthy volunteers. ClinicalTrials.gov identifier: NCT00880750.
磷结合剂通常以片剂形式用于帮助高磷血症患者限制其对饮食中磷的吸收。这些患者经常有沉重的片剂负担，因此替代制剂提供了选择，并且可能支持依从性。 碳酸镧（LC）是一种目前可用作咀嚼片的磷结合剂。 进行这项研究是为了支持在欧盟申请口服粉末制剂的营销许可。
本研究的目的是研究 LC 口服粉末制剂与参考咀嚼片制剂的药效学、药代动力学和耐受性。
一项在 18 至 55 岁接受标准化磷酸盐含量饮食的健康成年人中进行的 I 期、单中心、随机、开放标签、2 期、交叉研究，以评估两种制剂的药效学等效性。 个体在每个周期中随机接受不同的制剂，每个周期接受 10 次 1000mg LC，剂量为 3000mg/d，每个周期之间洗脱期≥14 天。主要药效学变量是接受 LC 时 3 天内尿磷的平均日排泄量。如果制剂之间的最小二乘（LS）均值排泄的尿磷差异的 90%置信区间（CI）在片剂制剂 LS 均值的±20%范围内，则确认药效学等效性。次要终点包括通过记录不良事件确定药代动力学参数和评估耐受性。
共有 72 人进入研究。 他们主要是男性（72.2%），平均（SD）年龄为 31.4（8.26）岁，BMI 为 25.8（2.45）kg/m 2。 LC 片剂给药时 LS 均值（SE）排泄的尿磷为 16.8（0.48）mmol/d（±20%=±3.35mmol/d）。LC 口服粉末给药时的相应值为 15.2（0.48）mmol/d；制剂之间差异的 90%CI 为-2.38 至-0.82mmol/d，确认药效学等效性。最常见的不良事件是胃肠道，未记录严重不良事件。
在这项多剂量研究中，LC 的口服粉末和片剂制剂在这些健康志愿者中耐受良好，符合药效学等效性的监管标准。临床Trials.gov 标识符：NCT00880750。
