Clinical trial NCT01740713
Conditions: Chronic Iron Overload
Keywords: chronic iron overload hereditary haemoglobinopathy beta thalassaemia major
Sponsor: Consorzio per Valutazioni Biologiche e Farmacologiche
Start date: 2012-12-01; Completion date: 2014-02-01
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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.

Arms: arm 1: single dose level of 8.3 mg/kg every 8 hours for a corresponding total daily dose of 25 mg/kg/day. arm 2: single dose level of 16.7 mg/kg every 8 hours for a corresponding total daily dose of 50 mg/kg/day. arm 3: single dose level of 33.3 mg/kg every 8 hours for a corresponding total daily dose of 100 mg/kg/day.
Interventions: intervention 1: Deferiprone, dose level 1 intervention 2: Deferiprone, dose level 2 intervention 3: Deferiprone, dose level 3
Intervention descriptions: intervention 1: a solution at 80 mg/mL will be administered orally intervention 2: a solution at 80 mg/mL will be administered orally intervention 3: a solution at 80 mg/mL will be administered orally

Protocol documents: