Abstract
PURPOSE: rhIL-7-hyFc (Efineptakin alfa) is a novel, long-acting recombinant human interleukin-7 developed to enhance immune responses by correcting T-cell deficiencies through increased lymphocyte counts. This study aimed to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model to support selection of the recommended Phase 2 dose (RP2D) through optimization of dosing regimens. PATIENTS AND METHODS: Serum rhIL-7-hyFc concentrations and absolute lymphocyte counts (ALC) were collected from 35 patients with solid tumors enrolled in a Phase Ib clinical trial (NCT03478995), who received multiple intramuscular administrations of rhIL-7-hyFc at doses ranging from 0.06 to 1.7 mg/kg every 3 or 6 weeks. A sequential mixed-effects PK-PD model was developed using NONMEM(®) (version 7.4.3) based on individual PK parameters. Monte Carlo simulations with extended dosing intervals up to 12 weeks were conducted to explore serum concentration profiles, ALC dynamics over time, and exposure-response relationships. RESULTS: The PK data were best described by a two-compartment model with first-order absorption from two depot compartments, and inter-occasional variability in clearance was incorporated in the final model. To account for the time-delayed response, the PD model utilized a series of transit compartments representing lymphocyte maturation. The stimulatory effect of rhIL-7-hyFc on progenitor cell proliferation was described using a simple maximum effect model. The estimated half-maximum effective concentration (EC(50)) was 0.066 ng/mL, indicating a high potency in increasing serum lymphocyte levels. Monte-Carlo simulation based on the final PK-PD model showed a dose-dependent increase in ALC. A dose range of 0.6-1.2 mg/kg administered at intervals of 6 to 12 weeks was suggested as feasible for the RP2D in further clinical trials. CONCLUSION: A population PK-PD modeling and simulation results demonstrated a strong exposure-response relationship for ALC across dosing intervals, underscoring the mechanism-based therapeutic potential of rhIL-7-hyFc in cancer immunotherapy.