Heeyoon Jung (1)†, Sang Won Lee (2)†, Woojin Jung (3), Lien Thi Ngo (3), Anhye Kim (4)*, Jung-woo Chae (1) (3)*, Hwi-yeol Yun (1) (3)*, Howard Lee (5)*
(1) Department of Bio-AI Convergence, Chungnam National University, Daejeon, Republic of Korea. (2) Hanyang University Hospital, Department of Clinical Pharmacology and Therapeutics, Seoul, Republic of Korea. (3) College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea. (4) Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea. (5) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
Objectives: The rhIL-7-hyFc (hybrid Fc-fused recombinant human interleukin-7; efineptakin alfa) is a homodimeric interleukin-7 (IL-7) fused to the hybrid Fc (hyFc) region, which is composed by the human IgD/IgG immunoglobulin domain. [1] The IgG domain binds to the FcRn receptor and is rescued from the intracellular catabolism by the FcRn-mediated recycling process, resulting in a long half-life in humans. [2] When exogenous IL-7 is administered to human, it proliferates the T-cells and increases the absolute lymphocyte counts (ALC). However, IL-7 has a short half-life, and to overcome this instability and to provide a better therapeutic effect, rhIL-7-hyFc was developed. Currently, phase 1 and 2 clinical trials are ongoing to evaluate the safety and efficacy in several chemotherapy-induced lymphopenia. For biological drugs, the drug-target binding may affect the pharmacokinetics (PK). [3] Thus, the purpose of this study was to develop a PK model of rhIL-7-hyFc that characterizes the TMDD (target-mediated drug disposition) and the FcRn-mediated recycling, and to explore the PK differences in various dosing regimen for chemotherapy-induced lymphopenia.
Methods: Serum concentrations of IL-7 were collected from a randomized clinical trial with a single administration of rhIL-7-hyFc in subcutaneous (20, 60 μg/kg, s.c.) and intramuscular (60 μg/kg, i.m.) routes to healthy patients, from screening to 672 hours after the doses. The semi-mechanistic PK modeling was conducted using nonlinear mixed-effects modeling (NONMEM, version 7.5, ICON plc, Dublin, Ireland) software assisted by Perl-speaks NONMEM (PsN, version 5.0.0). Various compartment models were explored with the first-order conditional estimation method with interaction estimation method (FOCE+I). The interindividual variability (IIV) was explained by exponential relationship. The residual variability (RV) was determined by additive, proportional, and combined models. The interaction of rhIL-7-hyFc and the IL-7 receptor (IL-7R) was characterized by the TMDD process. The interaction of rhIL-7-hyFc and the FcRn was also assumed to follow the TMDD process as well. The model was evaluated by the goodness of fit (GOF) and visual predictive check (VPC, n=1000) methods. Based on the final model, the simulation analysis was conducted. It has been reported from a phase 1 study of rhIL-7-hyFc (60, 120, 240, 540, 720, and 960 μg/kg, i.m., administered every 12 weeks (q12w)) for high-grade glioma patients treated with temozolomide, that the recommended phase 2 dose was 720 μg/kg q12w, due to dose-limiting toxicities at 960 μg/kg. [4] Thus, the simulated dose levels in our study covered these experimental (60 μg/kg, i.m.) and non-experimental (120, 240, 540, 720 μg/kg, i.m.) ranges in varying dosing intervals.
Results: A semi-mechanistic PK model with Quasi-steady state (QSS) approximation was developed to simultaneously describe the TMDD and FcRn-mediated recycling process. The main assumption is that the concentration of the free unbound drug, the target, and the drug-target complex are balanced in the QSS condition. The model reasonably described the PK profiles of 24 subjects (8 subjects for each regimen). The GOF and VPC results showed the plausibility of the model. Based on the simulation results, the Cmax and AUC of 60 ~ 540 μg/kg q12w administration were compared to that of 720 μg/kg q12w. The Cmax and AUC increased linearly within the 60 ~ 720 μg/kg dose range. Secondly, an exploration for lower dose regimens that would result in a similar Cmax and AUC to 720 μg/kg q12w was conducted. To achieve a similar Cmax to 720 μg/kg q12w, considerably shorter intervals were required (240 μg/kg q24 ~ q48hr, 540 μg/kg q72h ~ q96h). In addition, administration of 60 μg/kg q144h, 120 μg/kg q2w, 240 μg/kg q3w, 540 μg/kg q6w ~ q7w was required to achieve the similar AUC to that of 720 μg/kg.
Conclusions: In this study, we developed a semi-mechanistic TMDD model with QSS approximation, that simultaneously characterized the interaction of rhIL-7-hyFc and the IL-7R, as well as the FcRn-mediated recycling. We have also conducted a simulation study to compare the PK of different dosing regimens. To this day, various dose-finding studies are ongoing to assess the safety and efficacy of rhIL-7-hyFc for chemotherapy-induced lymphopenia. These results may be useful in designing future research.
† These authors contributed equally to this work as first-presenter.
* These authors contributed equally to this work as correspondence.
Acknowledgements:
This study was supported by Genexine Inc.
This study was supported by Institute of Information and Communications Technology Planning and Evaluation grant funded by the government of the Republic of Korea (MSIT; No. 2020-0-01441, Artificial Intelligence Convergence Research Center, Chungnam National University).
This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2022R1A2C1010929).
References:
[1] Lee, S. W., Choi, D., Heo, M., Shin, E. C., Park, S. H., Kim, S. J., Oh, Y. K., Lee, B. H., Yang, S. H., Sung, Y. C., & Lee, H. (2020). hIL-7-hyFc, A Long-Acting IL-7, Increased Absolute Lymphocyte Count in Healthy Subjects. Clinical and translational science, 13(6), 1161–1169.
[2] Sockolosky, J. T., & Szoka, F. C. (2015). The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy. Advanced drug delivery reviews, 91, 109–124.
[3] Gibiansky L, Gibiansky E, Kakkar T, Ma P. (2008) Approximations of the target-mediated drug disposition model and identifiability of model parameters. J Pharmacokinet Pharmacodyn, 35(5), 573-91.
[4] Campian J. L., et al. (2021). A phase I/II study to evaluate the safety and efficacy of a novel long-acting interleukin-7, NT-I7, for patients with newly diagnosed high-grade gliomas after chemoradiotherapy: The interim result of the phase I data. Journal of Clinical Oncology 39(15_suppl): 2040-2040.
Reference: PAGE 30 (2022) Abstr 10032 [www.page-meeting.org/?abstract=10032]
Poster: Drug/Disease Modelling - Oncology