A concatenated 3-compartment pharmacokinetic (PK) model describing concentrations of avalgucosidase alfa (AvGα) in patients with late-onset Pompe disease (LOPD) was created and described in a study published in Therapeutic Drug Monitoring.

Using pooled population PK (PopPK) data from 3 clinical trials, a plasma drug concentration curve with 2 kinetic sequences was identified. The first phase involved a sharp increase in concentration during the infusion process followed by a steep decline that reached a minimum between 10 and 16 hours. After this, a second kinetic phase showed a slow rebound that peaked around 72 hours and existed at low concentrations up to 336 hours.

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“A concatenated 3-compartment PopPK model was developed to characterize AvGα concentrations determined through enzymatic activity in the plasma of adolescent and adult patients with LOPD. This model could simultaneously fit the main kinetic phase and the slight rebound of the drug plasma concentration observed between 24 and 90 hours,” the authors wrote.

The population drug-time concentration curves suggested 2 different clearance processes, including a linear phase and a saturable clearance process. Tests of several screening models identified a 3-compartment model that best described the concentration curves. The model utilized a central compartment with 2 peripheral components with a drug back-redistribution between the second peripheral component and the central component.

The final model involved 9 parameters, including CL, Km, and Vmax, which described the 2 parallel clearances from the central compartment, as well as, V1, V2, V3, Qpc, Q2, and Q3, which described the drug distributions.

Using the model, simulations involving a typical individual weighing 70 kg were performed for 3 different enzyme doses including 5, 10, and 20 mg/kg. The simulation results along with actual observed concentration data showed that the primary drug exposure occurred during the first phase and that the second kinetic sequence only contributed marginally to exposure.

“These PopPK results support the approval of the 20 mg/kg Q2W dosing regimen for AvGα therapy in adult patients with LOPD by several health authorities,” the investigators wrote.

The 3 studies included 75 patients with LOPD and 2042 plasma concentration samples in the PopPK analyses. Doses of 5 mg/kg were administered to 8 patients, 10 mg/kg were given to 7 patients, and 70 patients received 20 mg/kg doses across the 3 trials.


Tuffal G, Tiraboschi G, Hurbin F, et al. Population pharmacokinetic modeling and determination of individual exposure to avalglucosidase Alfa in adolescent and adult patients with late-onset Pompe disease: Analysis of pooled data from phase I to III clinical trials. Ther Drug Monit. Published online August 1, 2023. doi:10.1097/ftd.0000000000001086