Population pharmacokinetics and dosing recommendations for the use of deferiprone in children younger than 6 years

Abstract

Aims: Despite long clinical experience with deferiprone, there is limited information on its pharmacokinetics in children aged <6 years. Here we assess the impact of developmental growth on the pharmacokinetics of deferiprone in this population using a population approach. Based on pharmacokinetic bridging concepts, we also evaluate whether the recommended doses yield appropriate systemic exposure in this group of patients.

Methods: Data from a study in which 18 paediatric patients were enrolled were available for the purposes of this analysis. Patients were randomised to three deferiprone dose levels (8.3, 16.7 and 33.3 mg kg^-1 ). Blood samples were collected according to an optimised sampling scheme in which each patient contributed to a maximum of five samples. A population pharmacokinetic model was developed using NONMEM v.7.2. Model selection criteria were based on graphical and statistical summaries.

Results: A one-compartment model with first-order absorption and first-order elimination best described the pharmacokinetics of deferiprone. Drug disposition parameters were affected by body weight, with both clearance and volume increasing allometrically with size. Simulation scenarios show that comparable systemic exposure (AUC) is achieved in children and adults after similar dose levels in mg kg^-1 , with median (5-95^th quantiles) AUC values, respectively, of 340.6 (223.2-520.0) μmol l^-1 h and 318.5 (200.4-499.0) μmol l^-1 h at 75 mg kg^-1 day^-1 , and 453.7 (297.3-693.0) μmol l^-1 h and 424.2 (266.9-664.0) μmol l^-1 h at 100 mg kg^-1 day^-1 given as three times daily (t.i.d.) doses.

Conclusions: Based on the current findings, a dosing regimen of 25 mg kg^-1 t.i.d. is recommended in children aged <6 years, with the possibility of titration up to 33.3 mg kg^-1 t.i.d.

Keywords: deferiprone; dose rationale; paediatrics; pharmacokinetic bridging; thalassaemia.

Figure 1

Pharmacokinetic model diagnostics. Goodness‐of‐fit plots. Upper panels show the observed data (Obs) vs. individual predictions (IPred) (left) and the observed data vs. population predictions (Pred) (right). Lower panels show the conditional weighted residuals (CWRES) vs. population predictions (left) and the CWRES vs. time (left)

Figure 2

Deferiprone concentration vs. time profiles. Visual predictive check: observed data are plotted using blue circles; the black solid line represents the median of the simulated data; the red dashed lines represent the 5th and 95th percentiles of the simulated data. The left, mid and right panels show, respectively, dose groups 1 (8.3 mg kg⁻¹), 2 (16.7 mg kg⁻¹) and 3 (33.3 mg kg⁻¹)

Figure 3

Predicted deferiprone exposure expressed as AUC_0–8 (upper panel), C_max (mid panel) and C_ss (lower panel) for children aged <6 years receiving 75 mg kg⁻¹ day^–1. The black line represents the median of the reference population (adult thalassaemic population), whereas the orange lines represent first and third quartiles and the red lines represent 5^th and 95^th percentiles of the same reference population. Percent of total indicates the percentage of cases for each beam of 1000 simulations with 100 patients in each simulated trial

Figure 4

Predicted deferiprone exposure expressed as AUC_0–8 (upper panel), C_max (mid panel) and C_ss (lower panel) for children younger than 6 years receiving 100 mg kg⁻¹ day^–1. The black line represents the median of the reference population (adult thalassaemic population), whereas the orange lines represent first and third quartiles and the red lines represent 5^th and 95^th percentiles of the same reference population. Percent of total indicates the percentage of cases for each beam of 1000 simulations with 100 patients in each simulated trial