Seohyeon Park1, Sang Min Lee1, Kwan Cheol Pak1, Mi-Sun Byun2, Donghoon Choi3, Hyeongseok Lim1
1Department of Clinical Pharmacology and Therapeutics, University of Ulsan / Asan Medical Center, 2Genexine Inc., 3NeoImmuneTech, Inc.
Objective: rhIL-7-hyFc (Efineptakin alfa) is a newly developed long-acting recombinant human interleukin-7, designed to amplify and enhance the number of T cells, thereby reinvigorating persistent T cell immunity by increasing the lymphocyte count of patients [1]. The aim of this study was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model to investigate the optimal dosing regimen for multiple intramuscular administration of rhIL-7-hyFc. Methods: The serum rhIL-7-hyFc concentration and absolute lymphocyte count (ALC) were obtained from 35 patients with solid tumors who received multiple intramuscular doses of rhIL-7-hyFc at 60, 120, 240, 480, 720, 960, 1200, and 1700 µg/kg every 3-week in a phase Ib clinical trial (NCT03478995). Mixed effects PK-PD model was established sequentially with NONMEM® (version 7.4.3.) using individual PK parameters [2]. Monte-Carlo simulations were performed to explore the relationship between serum concentration of rhIL-7-hyFc and changes in lymphocyte count over time. Results: Two-compartment linear model with 1st order absorption kinetics from two depot compartments and combined additive and proportional residual model best described the observed PK data [3]. The introduction of a two-depot model, where each dose was administered in two fractions with a time interval, effectively described the double peaks during the absorption phase. The PK model also included a random effect parameter for inter-individual variability (IIV) in bioavailability. The pre-dose PK measurements just before the start of rhIL-7-hyFc administration were included in the analysis dataset without treating missing value since the endogenous IL-7 concentrations could not be distinguished from the exogenous IL-7 in the enzyme-linked immunosorbent assay (ELISA) [4]. Inter-occasional variability on clearance was included in the final model [5]. Sex was found to be the only statistically significant covariate associated with clearance [6]. The PD model incorporated a series of transit compartments to represent the production and elimination of circulating lymphocytes in blood, including progenitor cell proliferation, maturation and lymphocyte circulation [7]. rhIL-7-hyFc was implemented to stimulate the proliferation of progenitor cells following a simple maximum effect model. This model well described the observed absolute lymphocyte change over time. The concentration at half maximum effect (EC50) in the maximum effect model was estimated to be as low as 0.069 ng/ml, which suggests that rhIL-7-hyFc is very potent. Conclusions: The current modeling and simulation well characterized the PK-PD profile and rhIL-7-hyFc showed a clear exposure-response relationship. The PK-PD model suggests that rhIL-7-hyFc is expected to exert pharmacologic effect at relatively low doses. The duration of the effect was predicted to be sufficient to sustain elevated ALC levels across various dosing regimens explored in this simulation study. This quantitative information would be useful in guiding the further study of rhIL-7-hyFc.
[1] Ahn S et al., Cancer Med. 2023;12(6):6778-6787. [2] Karlsson MO et al., Clin Pharmacol Ther 2007; 82: 17-20. [3] Liang Zhao et al., J Clin Pharmacol. 2013; 53(3):314-25. [4] Kim et al., Antibody Therapeutics 2024; 7(2) 105–113. [5] Karlsson MO, Sheiner LB., J Pharmacokinet Biopharm. 1993; 21(6):735-50. [6] Acta Universitatis Upsaliensis. 2002; ISSN 0282-7484; 280. [7] Lena E Friberg et al., J Clin Oncol. 2002; 15;20(24):4713-21.
Reference: PAGE 33 (2025) Abstr 11539 [www.page-meeting.org/?abstract=11539]
Poster: Drug/Disease Modelling - Oncology