Physiologically-based pharmacokinetic modeling approach to support eliglustat development for pediatric patients with Gaucher disease

Background: Eliglustat, an oral drug for adults with Gaucher disease type 1 (GD1), is primarily metabolized by CYP2D6. The objective of this study was to characterize eliglustat pharmacokinetics (PK) in pediatric participants (2 to < 18 years) with GD1 and Gaucher disease type 3 (GD3) across all CYP2D6 phenotypes using a physiologically-based pharmacokinetic (PBPK) model.Methods: A PBPK model was established with physicochemical parameters, in vitro, and in vivo clinical data including the enzyme kinetics metabolism, and the dynamic competitive and mechanism-based inhibition of CYP2D6 using SimCYP software [1, 2]. Clinical data used for model development included eliglustat PK from a Phase 3 (ELIKIDS; NCT03485677), open-label, two-cohort, multicenter study to evaluate the safety, PK, and efficacy of eliglustat monotherapy or in combination with imiglucerase in pediatric participants with GD1 and GD3. The pediatric PBPK model was developed and validated with the observed eliglustat pediatric PK data by adjusting the key input parameters from the adult PBPK model. Results: The PBPK model including age-dependent system parameters (ontogeny factors) aduquately characterized the observed eliglustat pediatric PK by adjusting the clearance for the pediatric population. The fraction value of drug metabolized by hepatic CYP enzymes relative to hepatic metabolism (fm) for CYP2D6 and CYP3A4 remained the same in adult and pediatric population. CYP2D6 abundance and variability values used for the CYP2D6 extensive (EM), intermediate (IM) and poor (PM) metabolizer virtual populations are assumed the same in two populations. The majority of individual observed concentrations in the pediatric patients were within the 5th to 95th percentile of the predicted concentration range within pediatric CYP2D6 EM patients. The overall prediction fold errors for the geometric mean PK parameters (i.e., Cmax and AUC0-τ) were < 1.2 to 1.5-fold. Simulated eliglustat exposure in pediatrics were comparable with the simulated or obseved exposure in adults at the corresponding approved doses across 3 CYP2D6 phenotypes (EM, IM and PM).Conclusions: The eliglustat pediatric PBPK model was optimized from the adult PBPK model and was successfully qualified using observed pediatric PK data.Citations: 1. Chen J, Turpault S, Kanamaluru V Physiologically based pharmacokinetic modeling for assessment of eliglustat interaction potential with CYP2D6 and CYP3A inhibitors. ASCPT abstract 20182. Chen J, Turpault S, Kanamaluru V Prediction of a lack of effect of eliglustat on a sensitive CYP3A substrate using physiologically-based pharmacokinetic modeling. ASCPT abstract 2018