Clinical pharmacologist Gilead Sciences Dublin, California, United States
Background: GS-3583 is a novel FMS-related tyrosine kinase 3 ligand (FLT3L) Fc fusion protein. FLT3L is a hematopoietic growth factor that binds to and activates FLT3 on differentiated dendritic cells. GS-3583 is being developed for the treatment of patients with solid tumors. A population pharmacokinetic (popPK) model was developed to describe GS-3583 PK and to assess the impact of clinically relevant covariates on GS-3583 exposure. Methods: The popPK analysis was performed on pooled data from a Phase 1 study in healthy volunteers (n=30, single IV dose from 0.075–2 mg), and a Phase 1b study in patients with solid tumors (n=13, multiple IV doses from 2–20 mg). Evaluated covariates included body weight, sex, ethnicity, race and disease status. Bodyweight-based allometric scaling was included via fixed exponents (0.75 for clearances and 1 for volumes of distributions). Results: GS-3583 exposure was greater than dose proportional in the evaluated dose range 0.075 mg to 6 mg and dose-proportional in 12 mg to 20 mg. A two-compartment disposition model with parallel nonlinear clearance and linear elimination could adequately describe GS-3583 PK. The typical values of clearance (CL), steady state volume of distribution (Vss), maximum rate (Vmax) and Michaelis constant (Km) were estimated to 0.0121 L/h, 5.57 L, 0.00658 mg/h and 0.0874 mg, respectively. Among the evaluated covariates, only disease status was found to be significant on Vmax. In the final model, all parameters and covariate effects were estimated with good precision ( < 40% RSE). No major bias or trends were observed in goodness-of-fit plots. Conclusion: The established popPK model adequately described GS-3583 PK. PopPK-based simulations were used to support clinical development of GS-3583.
