(M1530-11-65) Population Pharmacokinetic Modeling of Encapsulated Dexamethasone Sodium Phosphate in Autologous Erythrocyte (EryDex system) in the Treatment of Ataxia Telangiectasia

Purpose: Ataxia Telangiectasia (AT) is a rare, incurable, neurodegenerative disease and there is no treatment available that slows down or stops the progression of AT [1]. Steroid therapy has been effective to attenuate the neurological symptoms of this disease. However, neurological improvement disappears when oral steroid administration is discontinued. In addition, the benefit-to-risk balance limits the long-term administration of oral steroids due to typical steroid side effects. The administration of low doses of steroids through autologous erythrocytes has been shown to reduce steroid toxicity without compromising drug efficacy [2]. EryDex is a sustained release intravenous (IV) infusion system consisting of dexamethasone sodium phosphate (DSP) encapsulated in autologous erythrocytes, with the purpose of enabling administration of dexamethasone at stable low systemic levels over an extended period. The objective of this study was to characterize the pharmacokinetics (PK) of DSP from EryDex system by implementing a population PK modeling approach, and to investigate whether EryDex maintains sustained release of dexamethasone with sufficient plasma levels for a once monthly administration in AT treatment.

Methods: Dense plasma concentration-time PK data from IV infusion of EryDex in Phase 1 at two non-overlapping dose ranges of ~2.5-5 mg and ~15-20 mg DSP in healthy adults (age ≥ 17 years) and sparse PK data from Phase 3 (n=115) at two dose ranges of ~5-10 mg and ~14-22 mg DSP in AT pediatric patients were used in population PK model development. The PK data were analyzed using a nonlinear mixed effects modeling approach using NONMEM® 7.4 (Icon Development Solutions, Ellicott City, MD) implementing First-Order Conditional Estimation with Interaction (FOCE-I) algorithm. Various model structures were evaluated for describing the disposition of dexamethasone data: one-, two, and three-compartmental models with linear, nonlinear (Michaelis-Menten), or parallel linear and nonlinear elimination, as well as with linear, nonlinear (Michaelis-Menten), and dual absorption processes incorporating depot compartment, and semi-physiological models accounting for the dephosphorylation of DSP to dexamethasone within the enterocytes and subsequent passive diffusion of dexamethasone into the plasma. The final PK model was used to conduct Monte-Carlo simulations to generate rich sampling PK profiles over 6 dosing events, as one IV infusion per month for a total period of 6 months, in pediatric subjects, and at average dose values of 4.2 mg, 8.12 mg, and 17.30 mg DSP/Infusion.

Results: A two-compartmental model with linear elimination and allometric scaling of weight fixed to 0.75 on clearance from the central compartment (CL), and inter-compartmental clearance (Q), and to 1 on central (V1) and peripheral (V2) volumes of distribution was selected as the best structural model describing the observed PK data of Phase 1 and 3. In a stepwise covariate analysis, the effect of health status (healthy volunteers vs. patients) on CL was found to be statistically significant. This effect was estimated as 0.899 in the q^PTNTrelationship, where PTNT=0 and PTNT=1 stands for healthy subjects and patient population, respectively. Inter-individual variability was introduced only on CL and V1, as its addition on PK parameters of the second compartment did not improve model fit and would only over-parameterize the model. Two error models, one for each phase of the study, comprising additive and proportional components, were incorporated to describe the residual variability of the observed concentration-time profiles of dexamethasone. Alternatively, a two-compartmental semi-physiological model with linear elimination was successful in describing the dephosphorylation of DSP to dexamethasone within the RBCs, and sustained release of dexamethasone into the plasma of Phase 1 data (Figure 1). However, the goodness of fit of the model was not as adequate as the simpler two-compartmental model, and its population estimates for Q and associated inter-individual variability were unreasonable. This was attributed to the over-parameterization of the semi-physiological model when fitting sparse Phase 3 data (Figure 2). The slow release of dexamethasone was detected until 20-30 days after dosing even at low administered doses (Table 1). Nevertheless, no accumulation was observed in multiple dose administrations when the exposure measures from single and multiple dose (6-dose) regimens were compared.

Conclusion: Semi-physiological models are promising in describing the PK of drugs released from EryDex systems when adequate PK sampling data is available.  Simulated PK profiles demonstrated that EryDex provides long term release of dexamethasone, faster in the first 24 hours and much slower at low plasma concentrations over the following 20-30 days with no accumulation after multiple (six) administrations with a once monthly dosing regimen, positively impacting on both safety and efficacy of EryDex in long-term treatment of AT.

References: 1. Hoche F, Seidel K, Theis M, et al. Neurodegeneration in Ataxia Telangiectasia. What is New? What is Evident? Neuropediatrics 2012; 43(3):119-29. Epub 2012May21.
2. Rossi L, Castro M, D'Orio F, Damonte G, Serafini S, Bigi L, et al. Low doses of dexamethasone constantly delivered by autologous erythrocytes slow the progression of lung disease in cystic fibrosis patients. Blood Cells Mol Dis. 2004;33(1):57–63.

Acknowledgments: This project has been funded by EryDel S.p.A., Bresso (Milan), Italy (www.erydel.com).

Semi-physiological two-compartmental model



Goodness-of-Fit for (A) final PK model and (B) semi-physiological PK model of dexamethasone: population and individual predicted vs. observed concentrations (Phase 1 and Phase 3)



Multiple dose PK parameters of dexamethasone derived from simulated PK profile in pediatric patient population after the 6th dose (last dose)