Deferasirox Plasma Concentration Analysis and Effects of Potential Iron Chelators on Iron Overload and Safety Evaluation

Project: A - Government Institutionb - Ministry of Science and Technology

Project Details

Description

Thalassemia is a rare disease. Those anemia patients who need chronic blood transfusion usually become iron overloaded. The harmful effects of chronic iron overload can lead to damage of the liver, heart, and endocrine glands, resulting in organ compromise and death. Deferasirox (DFR), a potent and specific iron once-daily oral iron chelator, has been available for use in clinical practice in Taiwan since 2007. Although, it has been approved as first-line therapy for blood transfusion-related iron overload in certain countries, its efficacy and safety issues are still remained to be concerned especially in those DFR-treated patients with inadequate response. Aims of this proposal are to recruit patients who were inadequate responsive to once-daily DEFR and alternate their medication regimen to twice daily followed by therapeutic drug monitoring, to differentiate their specific biomarkers from responsive populations for outcomes prediction, and to employ in vitro drug screening assays and in vivo mice model of iron overload for drug developments to optimize iron chelation therapy. Study design: Due to serum ferritin is not a reliable indicator for iron deposition in organs, during the study year I, the correlation of plasma drug concentrations (DFR and its iron complex) at pre-dose and post-dose 2 h to patients’ serum ferritin and non-transferrin bound plasma iron (NTBI) will be determined while compared to MRI information. Reliable prognostic biomarkers for adequate responded vs. inadequate patients will be determined by proteome assays. Safety issues of DFR on patients’ renal and glucose tolerance will be monitored. Since iron overload has adverse effects on growth, during the study year II, prevalence of abnormal levels of certain sex hormones, hepcidin, labile hepatic iron, amino acids in long-term DFR-treated patients with or without herbal iron chelating agents will be evaluated by pharmacokinetics. Moreover, since T-type calcium channel blockers were reported to be non-traditional iron chelators with adverve effects on male fertility, during the study year III, in vitro assay system for dual activities of iron chelating and T-type calcium channel blocking, and in vivo diet induced iron overloaded thalassemia mice model will be utilized to test effects of hepcidin-mimetic agents or curcumin derivatives against iron depositions without compromise on male reproductive function. Safety concerns on male reproductive system will be approached by monitoring testosterone and sperm quality. In conclusion: Development of biochemical biomarkers (or indicators of iron contents) for patients with inadequate response and non-responded patients will be approached for early predicting the iron chelation responses in β-thalassemia patients while compared to the responded patients. The underlying mechanisms of the improved iron chelation therapy outcomes with various treatment regimens will be investigated by pharmacokinetics. Results from analysis of amino acids and novel peptide-hepcidin may provide alternative therapy for iron overloaded thalassemia patients. Combined therapy with novel iron chelators which are screened to possess in vitro dual iron chelating and moderate T-type calcium channel blocking activity may improve DFR’s iron deposition clearance from organs of iron overload in genetically-altered β-thalassemic mice.
StatusFinished
Effective start/end date8/1/137/31/14

Keywords

  • plasma deferasirox concentration analysis
  • iron overload control indicators
  • biomarkers
  • pharmacokinetics
  • male fertility of β-thalassemic mice
  • novel iron chelator