[P1–056]: POPULATION PHARMACOKINETIC‐PHARMACODYNAMIC (PK/PD) MODELING OF E2027, A SELECTIVE PHOSPHODIESTERASE‐9 (PDE9) INHIBITOR, FOLLOWING SINGLE ASCENDING ORAL DOSES IN HEALTHY VOLUNTEERS

To develop a population pharmacokinetic/pharmacodynamic (PPK/PD) model for E2027, a selective PDE9 inhibitor, following single ascending oral doses in healthy volunteers (HV), which will be used to drive dose selection in subsequent studies. Plasma concentration-time data of E2027, from a 4-part randomized, double blind, placebo-controlled, single ascending dose, Phase 1 study in HV, were subjected to population PK analysis by nonlinear mixed effect modeling. The effects of various baseline, demographic characteristics and dose on PK were evaluated. Post-hoc estimates of final PPK parameters were used in subsequent development of a population PK/PD (PPK/PD) model to describe the changes in cerebrospinal fluid (CSF) cGMP concentrations over time. The final PK and PPK/PD models were used to predict E2027 steady-state exposures and percent increase in CSF cGMP from baseline following multiple oral doses. The PK of E2027 was best described by a 2 compartment model with two input functions with five transit compartments, and first-order elimination. All parameters were estimated with good precision (CV% <10%). Weight, gender, and dose (>200 mg) significantly affected the PK of E2027. Percent CSF cGMP changes from baseline were best described by a sigmoidal inhibitory Emax model on kout, with IC50 of 118 ng/mL, and Imax of 0.813. Although, the PPK and PPK/PD models are being updated with PK and PD data from multiple ascending dose studies, simulations using the currently developed PPK/PD model suggest that once-daily E2027 dosed at, or above 100 mg should maintain cGMP at a 3-fold increase from baseline. A PPK/PD model for E2027 was successfully developed. This model supports selection of once daily doses for proof of concept studies, demonstrating target engagement that provides adequate CSF cGMP level elevations.