Pharmacokinetic Study of Deferiprone in Paediatric Patients
Condition: Chronic Iron Overload
MeSH terms: Hemoglobinopathies; Iron Overload
Study type: Interventional
Phase: Phase 2

Summary: 
      Deferiprone (DFP) is the most extensively studied oral iron chelator to date. It has been
      authorised in Europe in 1999 for the treatment of iron overload in patients with
      beta-thalassaemia major when DFO is contraindicated or inadequate. Despite a wide experience
      of DFP there are limited experimental data available on DFP in children and no
      pharmacokinetic data in children under 6 years of age. On the basis of the existing data in
      adults and adolescent, in the DEEP-1 trial a pharmacokinetic bridging model was developed to
      support the dose selection in children aged less than 6 years affected by transfusion
      dependent haemoglobinopathies. The study consisted of two phases, namely an experimental
      phase, during which patients received a single dose and a modeling phase, during which PK
      data obtained after single dose in patients < 6 years of age were analysed in conjunction
      with historical PK data in adults and older children and adolescents. The model-based
      analysis of the data obtained after single dose enabled the assessment of the dosing regimen
      required for the purpose of accurate pharmacokinetic bridging. The ratio between the
      predicted systemic exposure parameters (AUC and Cmax) in the target population and reference
      group were used as basis for recommendation of the dose in the target population.
    

Detailed description: 
      Deferiprone (DFP) was investigated as therapy for children from 1 month to less than 6 years
      of age. The study was a multicenter randomised, single blind, and single dose PK study. The
      patients were randomised according to a stratification scheme in which three different dose
      levels were used.

      Objectives: The primary objective of this study was to assess the pharmacokinetics of DFP in
      paediatric patients aged from 1 month to less than 6 years.

      The secondary objectives of this study were:

        1. To identify dose levels yielding deferiprone exposures comparable to adults and define
           the dose rationale in children aged from 1 month to less than 6 years.

        2. To evaluate safety and tolerability of deferiprone after single dose administration in
           children aged from 1 month to less than 6 years.

        3. To evaluate the effect of demographic covariates on DFP disposition and estimate the
           clearance distribution across the population.

      Endpoints: The primary endpoints of the study were pharmacokinetic and included:

        -  primary PK parameters: CL/F, Vd/F, Ka

        -  secondary PK parameters: AUC, Cmax, Tmax, Css and Cmin.

      Secondary endpoints were assessment of clinical safety and tolerability .

      Methods: Twenty-three patients were enrolled and 18 of those ( 9 males and 9 females)
      completed the study. The patients were administered at three dose levels ( 6 patients / each
      dose):

      Dose level 1: 8.3 mg/kg as a single dose (every 8 h) for a total daily dose of 25mg/kg Dose
      level 2: 16.7 mg/kg as a single dose (every 8 h) for a total daily dose of 50 mg/kg Dose
      level 3: 33.3 mg/kg as a single dose (every 8 h) for a total daily dose of 100 mg/kg

      Blood samples for PK analysis were taken at 6 sampling time intervals, different depending on
      the dose group: predose; in the range 10 -20 min; in the range 40-55min; in the range
      1.05-1.15 h;in the range 1.25-5.30 h;in the range 6-8h after the first dose administration.
      The concentration of deferiprone was determined by a validated HPLC method. A population PK
      model approach was applied and the time course of deferiprone concentrations was analysed
      with Nonlinear mixed effects modelling in NONMEM, version 7.2.0. Model building included the
      assessment of the influence of relevant demographic covariates (i.e:body weight , age,
      height) on the disposition of deferiprone.

      Using the pharmacokinetic model developed for the paediatric population in this study in
      conjunction with a model previously developed for 55 adult subjects , simulations were
      performed to evaluate drug exposure in children below 6 years of age and across a standard
      thalassaemic adult population.

      Descriptive statistics were used to summarise adverse events, vital signs and clinical lab
      data (haematology, biochemistry and virology)

      Results: A one-compartment model with first-order absorption was found to best describe the
      disposition of deferiprone. The choice of three dose levels enable to assess linearity of
      pharmacokinetic across the dose range. The disposition parameters estimated through the
      pop-PK model included CL/F , V/F. In addition to the final model parameter estimates, the
      secondary pharmacokinetic parameters were derived based on the individual predicted
      concentration vs. time profiles and were summarised per dose level.

      Body weight was found to be a good predictor of inter-individual differences in the
      population under investigation.

      As expected from the known safety profile of the drug, no Serious Adverse Events were
      observed during the DEEP-1 PK Study.

      Based on the simulation analysis performed, a similar exposure is achieved in adults and
      children in terms of AUC and Css when receiving the current dosing regimen both at 75 and 100
      mg/kg/day, while a considerable increase in Cmax was observed in children when compared to
      the adult population. However, exposure is the parameter related to clinical response rather
      than Cmax. Indeed, simulations suggested that a dosing regimen of 25 mg/kg t.i.d. (75
      mg/kg/day) is recommended for children aged from 1 month to < 6 years, with the possibility
      of titration up to 33.3 mg/kg t.i.d. (100 mg/kg/day), if necessary.
    

Intervention name(s): Deferiprone, dose level 1; Deferiprone, dose level 2; Deferiprone, dose level 3
Intervention type(s): Drug; Drug; Drug
Intervention description(s): a solution at 80 mg/mL will be administered orally; a solution at 80 mg/mL will be administered orally; a solution at 80 mg/mL will be administered orally
Other intervention name(s): DFP; DFP; DFP
Intervention MeSH terms: Deferiprone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Keywords: chronic iron overload; hereditary haemoglobinopathy; beta thalassaemia major