Learn and Confirm Inc., 3630 Bois Franc, St-Laurent QC, Canada. Université de Montréal, Faculté de pharmacie, Pavillon Jean Coutu, 2940 Chemin de la polytechnique, Montreal QC, Canada.
J Pharm Pharm Sci. 2013;16(3):424-40. doi: 10.18433/j3hs42.
Iron-containing products are atypical in terms of their pharmacokinetic properties because iron is only removed by plasma sampling and is non-linear. This study aims to present a novel way of assessing the relative bioavailability of two sodium ferric gluconate complex (SFGC) formulations and compare this approach to a standard previously published noncompartmental approach.
Data were from open-label, randomized, single-dose studies (Study 1 was parallel whereas Study 2 was crossover). Subjects with low but normal iron levels were infused IV SFGC in sucrose by GeneraMedix Inc. and/or Ferrlecit ® Injection (Watson Laboratories Inc.). In Study 1 (n=240), 125 mg was infused over 10 minutes. In Study 2 (n=29), 62.5 mg was infused over 30 minutes. Samples were assayed for total iron (TI) and transferrin-bound iron (TBI) over 36 hours (Study 1) or 72 hours (Study 2) post-dose. Studies 1 and 2 used standard noncompartmental analysis. Study 2 also used population PK (PPK) analyses with ADAPT 5®. The final model predicted SFGC area-under-the-curve (AUCpred) and maximal concentration (Cmaxpred). Analyses of variance was conducted on ln-transformed PK parameters. Ratios of means and 90% confidence intervals (CIs) were estimated. Bioequivalence was demonstrated if values were within 80-125%.
For Study 1, ratios and 90% CIs for TI baseline-corrected Cmax and AUC0-36 were 100.4 (96.5 - 104.5) and 99.7 (94.2 - 105.5). For TBI, results for TI baseline-corrected Cmax and AUC0-36 were 86.8 (82.7 - 91.1) and 92.4 (85.6 - 99.7). For Study 2, a multi-compartmental model simultaneously described the PK of TI, TBI and SFGC. Ratios and 90% CIs for SFGC Cmaxpred and AUCpred were 89.9 (85.9 - 94.0) and 89.7 (85.7 - 93.9), while ratios and 90% CI obtained from the noncompartmental analysis of Study 2 did not meet BE criteria because of low power.
Both the standard and PPK modeling approach suggested bioequivalence between the iron products. However, with the PPK method, less subjects were required to meet study objectives compared to the standard noncompartmental approach which required considerably more subjects (29 vs 240).
铁制剂在药代动力学特性方面是非典型的，因为铁只能通过血浆取样去除且呈非线性。本研究旨在提出一种评估两种葡甲胺铁复合物（SFGC）配方相对生物利用度的新方法，并将该方法与之前发表的标准非房室分析方法进行比较。
数据来自开放标签、随机、单剂量研究（研究 1 为平行，研究 2 为交叉）。受试者的铁水平较低但正常，由 GeneraMedix Inc. 和/或 Ferrlecit®注射剂（Watson Laboratories Inc.）静脉输注 SFGC 蔗糖溶液。在研究 1（n=240）中，125mg 在 10 分钟内输注。在研究 2（n=29）中，62.5mg 在 30 分钟内输注。在给药后 36 小时（研究 1）或 72 小时（研究 2）内，对总铁（TI）和转铁蛋白结合铁（TBI）进行采样。研究 1 和 2 均采用标准非房室分析。研究 2 还使用 ADAPT 5®进行群体药代动力学（PPK）分析。最终模型预测 SFGC 曲线下面积（AUCpred）和最大浓度（Cmaxpred）。对 PK 参数进行自然对数转换后进行方差分析。比值和 90%置信区间（CI）的估计。如果值在 80-125%范围内，则证明生物等效性。
对于研究 1，TI 基线校正的 Cmax 和 AUC0-36 的比值和 90%CI 分别为 100.4（96.5-104.5）和 99.7（94.2-105.5）。对于 TBI，TI 基线校正的 Cmax 和 AUC0-36 的结果分别为 86.8（82.7-91.1）和 92.4（85.6-99.7）。对于研究 2，多房室模型同时描述了 TI、TBI 和 SFGC 的 PK。SFGC Cmaxpred 和 AUCpred 的比值和 90%CI 分别为 89.9（85.9-94.0）和 89.7（85.7-93.9），而来自研究 2 的非房室分析获得的比值和 90%CI 由于效力较低而不符合 BE 标准。
标准和 PPK 建模方法均表明两种铁制剂具有生物等效性。然而，与需要更多受试者（29 比 240）的标准非房室分析方法相比，PPPK 方法需要较少的受试者即可达到研究目标。
