Novel Population Pharmacokinetic Method Compared to the Standard Noncompartmental Approach to Assess Bioequivalence of Iron Gluconate Formulations

Abstract

-Purpose: 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. Methods: Data were from openlabel, 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-underthe-curve (AUC pred ) and maximal concentration (Cmax pred ). Analyses of variance was conducted on lntransformed PK parameters. Ratios of means and 90% confidence intervals (CIs) were estimated. Bioequivalence was demonstrated if values were within 80-125%. Results: For Study 1, ratios and 90% CIs for TI baseline-corrected Cmax and AUC 0-36 were 100.4 (96.5 -104.5) and 99.7 (94.2 -105.5). For TBI, results for TI baseline-corrected Cmax and AUC 0-36 were 86.8 (82.7 -91.1) and 92.4 (85.6 -99.7). For Study 2, a multicompartmental model simultaneously described the PK of TI, TBI and SFGC. Ratios and 90% CIs for SFGC Cmax pred and AUC pred 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. Conclusions: 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).

Opportunities and Challenges Related to the Implementation of Model‐Based Bioequivalence Criteria

“…63,64 Besides the previously described examples related to alendronate (fitting the urinary excreted amounts), corticosteroids (using the skin blanching study guidance), and albuterol (using FEV 1 and the dose scale approach), we have also proposed the use of the population approach for other specific cases (topical acyclovir, cyclosporine, and iron gluconate), which will not be described further as their methodology and results have been described extensively elsewhere. [65][66][67] In the studies involving cyclosporine and iron gluconate, a direct comparison was made between results obtained by the compartmental and NCPT methods, and the conclusions that were reached by both approaches were similar.…”

“…Model directly incorporates and addresses characteristics that are not related to the formulation performances allowing a more robust assessment of BE. In the case of iron products, this approach seems to require a much lower sample size compared to NCPT analysis 67…”