Population Pharmacokinetics of Alfusozin in children and adolescents
D Fabre (1), N Djebli (1), C Rauch(1)
(1) Modelling and Simulation entity, Drug Disposition Domain, Disposition, Safety and Animal research, Sanofi-Aventis R&D Montpellier, France
Objectives: The objective of this analysis was to develop and qualify a combined PopPK model for two formulations (solution and sustained release tablets) of alfuzosin administered in children and adolescents, and to investigate the influence of key demographic parameters (i.e., body weight, age, sex, race) and renal function (measured by ClCR) on alfuzosin PK.
Methods: The analysis was based on plasma samples from 3 pediatric clinical studies using the NONMEM computer program (version VI level 1.2) running on LINUX. All runs were performed using the FOCE method. Mono- and bi-compartmental models with and without lag time with zero or first order absorption were evaluated. Formulation was included as a straightaway covariate on Ka, in order to be able to develop a PopPK model for solution and tablet formulations, according to: ka(L/h)=TVKa+theta(6)*(1-Form).
Results: The data Set was composed of 209 patients (841 samples, age ranging from 2 to 17 years, weight from 10 to 90 kg), 134 receiving the solution (572 samples) and 75 the tablet (269 samples). The structural PK model was a bi-compartment model with a formulation-dependent absorption constant (Ka, 0.0.0990 h-1 for tablet and 0.293 h-1 for solution), characterizing the first-order absorption process from the depot to the central compartment. Oral clearance was 7.88 L/h and was related to body weight according to:CL/F(L/h)=7.88+0.535*WT . Oral distribution volume V2/F was 12.9 L. The peripheral compartment was related to the central one by an inter-compartmental clearance Q/F of 5.7 L/h and described by an apparent distribution volume V3/F of 185 L. Inter-patient variability in the CL/F, V2/F and V3/F and ka was about 42.2 %, 57.5 %, 159 % and 39.0 %, respectively. The residual variability was about 36.5 %.
Sex, Age, Race, CLCR and Dose (0.1 or 0.2 mg/kg/day) had no influence on alfuzosin PK.
Conclusions: A PopPK model was developed and validated with data from 209 patients of 3 pediatric studies treated with alfuzosin solution or tablet formulations at 0.1 or 0.2 mg/kg/day. This model, parameterized as a 2-compartment model with first-order formulation-dependent absorption process, showed a good agreement between predicted and observed plasma concentrations for solution and tablet.