title: Novel population pharmacokinetic method compared to the standard noncompartmental approach to assess bioequivalence of iron gluconate formulations.
abstract: OBJECTIVE
  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 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%.
  
  
  RESULTS
  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.
  
  
  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).
authors.affiliation: 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.
authors.forename: Corinne
authors.initials: C
authors.lastname: Seng Yue
authors.forename: Keith
authors.initials: K
authors.lastname: Gallicano
authors.forename: Line
authors.initials: L
authors.lastname: Labbé
authors.forename: Murray P
authors.initials: MP
authors.lastname: Ducharme
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D005260:Female; D005290:Ferric Compounds / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D005290:Ferric Compounds; C035552:ferric gluconate