title: Model-Based Optimisation of Deferoxamine Chelation Therapy.
abstract: OBJECTIVE
  Here we show how a model-based approach may be used to provide further insight into the role of clinical and demographic covariates on the progression of iron overload. The therapeutic effect of deferoxamine is used to illustrate the application of disease modelling as a means to characterising treatment response in individual patients.
  
  
  METHODS
  Serum ferritin, demographic characteristics and individual treatment data from clinical routine practice on 27 patients affected by β-thalassaemia major were used for the purposes of this analysis. The time course of serum ferritin was described by a hierarchical nonlinear mixed effects model, in which compliance was parameterised as a covariate factor. Modelling and simulation procedures were implemented in NONMEM (7.2.0).
  
  
  RESULTS
  A turnover model best described serum ferritin changes over time, with the effect of blood transfusions introduced on the ferritin conversion rate and the effect of deferoxamine on the elimination parameter (Kout) in a proportional manner. The results of the simulations showed that poor quality of execution is preferable over drug holidays; and that independently of the compliance pattern, the therapeutic intervention is not effective if >60% of the doses are missed.
  
  
  CONCLUSIONS
  Modelling of ferritin response enables characterisation of the dynamics of iron overload due to chronic transfusion. The approach can be used to support decision making in clinical practice, including personalisation of the dose for existing and novel chelating agents.
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bellanti
authors.affiliation: Azienda Ospedaliera Universitaria Consorziale, Policlinico di Bari, Bari, Italy.
authors.forename: Giovanni C
authors.initials: GC
authors.lastname: Del Vecchio
authors.affiliation: Azienda Ospedaliera di Padova, Clinica di Oncoematologia Pediatrica, Padova, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Putti
authors.affiliation: Azienda Ospedaliera Universitaria, Policlinico di Sassari,, Sassari, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Cosmi
authors.affiliation: Azienda Ospedaliera Universitaria, Policlinico di Sassari,, Sassari, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Fotzi
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: Suruchi D
authors.initials: SD
authors.lastname: Bakshi
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands. o.dellapasqua@ucl.ac.uk.|Clinical Pharmacology & Therapeutics, University College London, BMA House, Tavistock Square, WC1H 9JP, London, UK. o.dellapasqua@ucl.ac.uk.|Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, UK. o.dellapasqua@ucl.ac.uk.
authors.forename: Oscar
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D000293:Adolescent; D000328:Adult; D015913:Chelation Therapy / Q000379:methods*; D002648:Child; D003198:Computer Simulation; D003676:Deferoxamine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D017707:Erythrocyte Transfusion / Q000009:adverse effects; D005293:Ferritins / Q000097:blood*; D006801:Humans; D019190:Iron Overload / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D008954:Models, Biological; D017262:Siderophores / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult; D017086:beta-Thalassemia / Q000097:blood / Q000150:complications / Q000628:therapy*
chemical_list: D017262:Siderophores; D005293:Ferritins; D003676:Deferoxamine
keywords: PKPD modelling; adherence; deferoxamine; disease modelling; dose rationale; iron overload