Population pharmacokinetic modeling and dosing simulation of avalglucosidase alfa for selecting alternative dosing regimen in pediatric patients with late-onset pompe disease

AbstractAvalglucosidase alfa (AVAL) was approved in the United States (2021) for patients with late-onset Pompe disease (LOPD), aged  ≥ 1 year. In the present study, pharmacokinetic (PK) simulations were conducted to propose alternative dosing regimens for pediatric LOPD patients based on a bodyweight cut-off. Population PK (PopPK) analysis was performed using nonlinear mixed effect modeling approach on pooled data from thr ee clinical trials with LOPD patients, and a phase 2 study (NCT03019406) with infantile-onset Pompe disease (IOPD: 1–12 years) patients. A total of 2257 concentration-time points from 91 patients (LOPD, n = 75; IOPD, n = 16) were included in the analysis. The model was bodyweight dependent allometric scaling with time varying bodyweight included on clearance and distribution volume. Simulations were performed for two dosing regimens (20 mg/kg or 40 mg/kg) with different bodyweight cut-off (25, 30, 35 and 40 kg) by generating virtual pediatric (1–17 years) and adult patients. Cor responding simulated individual exposures (maximal concentration, Cmax and area under the curve in the 2-week dosing interval, AUC2W), and distributions were calculated. It was found that dosing of 40  mg/kg and 20 mg/kg in pediatric patients <  30 kg and ≥ 30 kg, respectively, achieved similar AVAL exposure (based on AUC2W) to adult patients receiving 20  mg/kg. PK simulations conducted on the basis of this model provided supporting data for th...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research