R. Yu,1 K. Luu,1 C. Bethune,1 S. Bhanot,1 Q. Liu,2 Y. Wang1; 1ISIS Pharmaceuticals, Inc., Carlsbad, CA, 2Takeda Pharmaceuticals, Deerfield, IL

BACKGROUND: To develop a population PK/PD model for an antisense Factor XI (FXI) inhibitor, ISIS-FXIRx, is currently being developed for the prevention and treatment of thromboembolic disease.
METHODS: Results from a Phase I clinical trial of ISIS-FXIRx in healthy subjects (n=88) were used for the population PK-PD analysis using NONMEM®. ISIS-FXIRx was administered as subcutaneous injections either as a single dose or multiple weekly with doses ranging from 50 to 400 mg for a duration of up to 6 weeks. The plasma concentrations of ISIS-FXIRx and serum FXI activity levels were measured at various time points during the treatment and follow-up period for 3 months after treatment was completed.
RESULTS: Plasma ISIS-FXIRx concentration-time course data were described with a two-compartment model and first order elimination. Typical estimates of plasma clearance (CLp), distribution volumes of central (V2) and peripheral (V3) compartments were 2.93 L/hr, 9.90 L and 164 L, respectively. Inter-subject variability was 26.9% for CLp, 32.6% for V2 and 33.2% for the absorption rate constant (Ka). Preliminary analyses did not show any significant covariate effects. Serum FXI activity levels were fitted to an indirect response model with a drug inhibitory effect on the zero order formation rate constant (Kin) for FXI activity level. The typical values for the model for Imax, IC50, baseline FXI activity level, the first order output rate constant for FXI activity level (Kout) and ╬│ were 1.0 (fixed), 12.4 ng/mL, 1.05 U/mL, 0.00153/hr and 1.44, respectively.
CONCLUSION: The developed population PK/PD model well described the plasma concentration-time course of ISIS-FXIRx and serum FXI activity profiles. This model has been used for trial simulation and dose optimization for future clinical studies.