Pilot Study for Patients With Poor Response to Deferasirox

The purpose of this trial is to examine three potential mechanisms of inadequate response to Exjade® in patients with transfusion dependent iron overload including patients with thalassemia syndromes, sickle cell disease and bone marrow failure.

Hypothesis: Patients have physiologic barriers to adequately respond to deferasirox that may include absorption, pharmacokinetics of drug metabolism, hepatic clearance and/or genetic factors.

Study objectives Primary objective

* To evaluate three potential mechanisms for inadequate response to deferasirox in a small cohort of patients with hemoglobinopathies.

* Oral pharmacokinetics measured with Cmax and AUC following standard dose deferasirox.

* Hepatobiliary excretory function

* Accessibility of chelatable iron pool by deferoxamine challenge Secondary objective(s)

* To identify risk factors that can predict adequate response including demographics, disease status, presence and severity of liver disease, trough levels of deferasirox at outpatient visits and pharmacogenomics.

* To investigate usefulness of potential surrogate measures of response including serum deferasirox levels, Hepatobiliary Iminodiacetic Acid (HIDA)nuclear medicine scan to evaluate hepatic excretory function and urinary iron excretion by deferoxamine challenge.

This is an investigator-initiated, pilot-scale, open-label physiological assessment of patients who respond poorly to deferasirox compared with patients who respond well. We plan to study 2 groups of patients: a)10 patients who have demonstrated poor responses and b) 5 control patients with good responses as defined further in the protocol. The study has two parts.

Part I: Both groups of patients will have inpatient physiological assessments with a dose of 35mg/kg of deferasirox.

Part II: Inadequate responders eligible to continue on deferasirox will continue on a dose of 35 mg/kg for three months during which time serial pharmacokinetic levels will be studied. The control patients will resume their previous clinically appropriate dosing (likely less than 35 mg/kg) and for three months have serial pharmacokinetic levels drawn as well.

The study will begin with an outpatient screening visit when demographics and historical information as well as a physical examination will be obtained and reviewed for eligibility. At that visit patients will be able to sign informed consent. Shortly thereafter patients will be admitted to the GCRC at Children's Hospital Boston for part I of the study, a 2-3 day stay during which PK and nuclear medicine studies will be performed as well as the deferoxamine urinary iron excretion challenge. Patients who are eligible will continue on to part II of the study, and for 3 months and will be monitored for compliance, PK and ferritin changes on appropriate deferasirox doses.

Primary Outcome Measures

1. Area Under the Curve of Deferasirox After a Dose of 35 mg/kg
   Area Under the Curve (AUC) 0 to 24 hours post dose
2. Half-Life of Deferasirox
   All patients received the same interventions of deferoxamine challenge, deferasirox dose with pharmacokinetic monitoring. Then we compared responses between patients who were known to be slow responders to deferasirox and those who were known to be rapid responders (chelated well). Deferoxamine: After a 3-day washout period from all chelation, all patients have a 12 hour infusion of 50mg/kg of deferoxamine with urine collection and pre and post blood sampling to assess iron and Total Iron Binding Capacity (TIBC) by atomic absorption.
3. Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg
   Volume of distribution/bioavailability (Vd/F)
4. Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg
   Volume of distribution/bioavailability (Vd/F), adjusted per kilogram body weight
5. Clearance/Bioavailability of Deferasirox in Patients With Poor Response to Deferasirox Compared to Patients With Good Response After a Dose of 35 mg/kg
   Clearance/bioavailability (CL/F)

Secondary Outcome Measures

1. Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition
   Polymorphisms in genes known to be, or potentially involved, in deferasirox disposition: UGT1a1 (including the Gilbert syndrome promoter polymorphism, (TA)nTAA),UGT1a3, BRCP/ABCG2, MRP2/ABCC2. These genes were chosen because deferasirox is primarily eliminated by glucuronidation and subsequent biliary excretion.