title: Iron uptake and ferrokinetics in healthy male subjects of an iron-based oral phosphate binder (SBR759) labeled with the stable isotope (58)Fe.
abstract: SBR759 is a novel polynuclear iron(III) oxide-hydroxide starch·sucrose·carbonate complex being developed for oral use in chronic kidney disease (CKD) patients with hyperphosphatemia on hemodialysis. SBR759 binds inorganic phosphate released by food uptake and digestion in the gastro-intestinal tract increasing the fecal excretion of phosphate with concomitant reduction of serum phosphate concentrations. Considering the high content of ∼20% w/w covalently bound iron in SBR759 and expected chronic administration to patients, absorption of small amounts of iron released from the drug substance could result in potential iron overload and toxicity. In a mechanistic iron uptake study, 12 healthy male subjects (receiving comparable low phosphorus-containing meal typical for CKD patients: ≤1000 mg phosphate per day) were treated with 12 g (divided in 3 × 4 g) of stable (58)Fe isotope-labeled SBR759. The ferrokinetics of [(58)Fe]SBR759-related total iron was followed in blood (over 3 weeks) and in plasma (over 26 hours) by analyzing with high precision the isotope ratios of the natural iron isotopes (58)Fe, (57)Fe, (56)Fe and (54)Fe by multi-collector inductively coupled mass spectrometry (MC-ICP-MS). Three weeks following dosing, the subjects cumulatively absorbed on average 7.8 ± 3.2 mg (3.8-13.9 mg) iron corresponding to 0.30 ± 0.12% (0.15-0.54%) SBR759-related iron which amounts to approx. 5-fold the basal daily iron absorption of 1-2 mg in humans. SBR759 was well-tolerated and there was no serious adverse event and no clinically significant changes in the iron indices hemoglobin, hematocrit, ferritin concentration and transferrin saturation.
authors.affiliation: Drug Metabolism & Pharmacokinetics (DMPK)/Integrated Drug Disposition (IDD), Novartis Pharma AG, 4002 Basel, Switzerland. hans-peter.gschwind@bluewin.ch.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Gschwind
authors.forename: Dietmar G
authors.initials: DG
authors.lastname: Schmid
authors.forename: Friedhelm
authors.initials: F
authors.lastname: von Blanckenburg
authors.forename: Marcus
authors.initials: M
authors.lastname: Oelze
authors.forename: Kirsten
authors.initials: K
authors.lastname: van Zuilen
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Slade
authors.forename: Sylvie
authors.initials: S
authors.lastname: Stitah
authors.forename: Daniel
authors.initials: D
authors.lastname: Kaufmann
authors.forename: Piet
authors.initials: P
authors.lastname: Swart
mesh_terms: D000293:Adolescent; D000328:Adult; D004338:Drug Combinations; D005290:Ferric Compounds / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D005293:Ferritins / Q000032:analysis; D006400:Hematocrit; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007503:Iron Isotopes / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D013213:Starch / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D014168:Transferrin / Q000032:analysis; D055815:Young Adult
chemical_list: D004338:Drug Combinations; D005290:Ferric Compounds; D006454:Hemoglobins; D007503:Iron Isotopes; C570356:SBR 759; D014168:Transferrin; D013213:Starch; D005293:Ferritins