Population Pharmacokinetic Modeling and Pediatric Exposure of Dexamethasone Sodium Phosphate Encapsulated in Erythrocytes (eDSP) Administered Monthly for Treatment of Neurological Symptoms of Patients With Ataxia Telangiectasia.

Abstract

The EryDex System (EDS) is a drug/device combination, which has been tested in clinical trials for ataxia telangiectasia (AT). EDS encapsulates dexamethasone sodium phosphate (DSP) solution in autologous erythrocytes at the point of care, and encapsulated DSP (eDSP) is infused back into the patient. Low doses of dexamethasone are released from erythrocytes over a 30-day period. This study aimed to (1) characterize the pharmacokinetics (PK) of dexamethasone released from intravenously infused eDSP based on data collected in clinical trials of healthy adults and pediatric AT patients, and to (2) simulate and extrapolate exposure measures of dexamethasone following intravenous infusion of eDSP administered once per month over 6 months in a pediatric population. The population PK model was developed using dense PK data from a phase 1 study in healthy adults and sparse PK data from a phase 3 study in pediatric AT patients. Three dose levels were studied, and the overall PK population included 24 healthy adults and 109 AT patients. The PK of dexamethasone released from eDSP was described using a simplified two-compartment model, adequate for estimating systemic exposure despite not fully capturing RBC release kinetics indicative of a triphasic pattern. The model showed a good fit, and future refinement will include mechanistic release modeling as more in vitro and in vivo data become available. Monte Carlo simulations of eDSP showed a rapid peak at 0.67 h, followed by sustained dexamethasone release; faster in the first 24 h, then slower over 20-30 days. No accumulation occurred with once-monthly dosing.