Seongmee Jeong(1), Ho Yeong Lim(2), Jin Seok Ahn(2), Joon Oh Park(2), Jung Yong Hong(2), Sung Young Lee(3), Sung Ho Kim(3), Heung Tae Kim(3), Soyoung Lee*(1), Jung-woo Chae＊(1),(4), Hwi-yeol Yun(1),(4)*
(1) College of Pharmacy, Chungnam National University, Daejeon, South Korea, (2) Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, (3) ImmuneOncia Therapeutics, Inc., Seoul, South Korea, (4) Bio-AI Convergence Research Center, Chungnam National University, South Korea *Those of authors contributed equally a s correspondence.
Objectives:
Target-mediated drug disposition (TMDD) model is used to describe a nonlinear pharmacokinetics (PK) phenomenon that is caused by high-affinity binding of a compound to its pharmacologic targets. [1] TMDD has received most interest as a saturable clearance mechanism for biologics, specifically monoclonal antibodies. [2]
IMC-002 is a fully human Immunoglobulin (Ig) G4 monoclonal antibody that targets cluster of differentiation 47 (CD47). It blocks the CD47-signal regulatory protein alpha interaction, thereby increasing phagocytosis of cancer cell by macrophages. During phase 1 clinical study, IMC-002 showed non-linear pharmacokinetics, which were due to in vivo mechanism of IgG. The neonatal Fc receptor for IgG (FcRn) binds to IgG to inhibit degradation by lysosome and recycles IgG through lymphatic pathway. The aims of study are to establish a PK model for IMC-002 to describe its non-linear pharmacokinetics and to optimize the dosage regimen for the phase 2 trial based on the PK model.
Methods:
PK data were obtained from a phase 1 dose escalation study of 12 patients with advanced solid tumors. Each subject received multiple doses of 5, 10, 20, and 30 mg/kg via intravenous infusion over 3 hours every 2 weeks. Population PK of IMC-002 was analyzed using NONMEM software (version 7.5) with the first order conditional estimation method with interaction (FOCE INTER). Assessment of model was applied through general modeling building criteria. (i.e. Objective function value, Goodness of fit plot, Visual predictive checks, etc.) Using a final model that well explains the pharmacokinetics of IMC-002, simulations of various scenarios (n=100, each dose level) were done to suggest the optimal dose regimen to maintain concentration above minimum effect concentration (MEC) for solid cancer patients.
Results:
For studies used in the model building, a total of 213 samples (free drug concentration) were used for analysis. Due to pharmacokinetic properties of antibodies, mechanism-based model is used rather than empirical based model. The final PK model of IMC-002 was described by full target-mediated drug disposition (TMDD) model with lymphatic circulation of IgG. The degradation constant of CD47 (0.0213 h-1), dissociation constant of CD47 (0.046 μM), dissociation constant of FcRn (0.117 μM), total receptor of FcRn (0.291 μM), and dissociation rate of drug-CD47 complex (90.4 h-1) were fixed using literature and in-house experimental data. Performance of final population PK model was acceptable. Parameter estimates were: synthesis rate of CD47 (0.0023 1/ μM*h-1), reuptake rate of IMC-002 (0.0096 h-1), recycling rate of drug-FcRn complex (0.0173 h-1), free drug clearance (0.0147 L/h), and elimination rate of drug-CD47 complex (0.017 h-1).
Using this model, half-life and clinical situation were took into consideration to make simulation scenarios. For simulations’ dosing regimen, each dose (5, 10, 20, and 30 mg/kg) was administered 5 times every 3 weeks through intravenous infusion. Adequate dosing regimen was confirmed to be 20 mg/kg which kept 80% of simulated data`s trough concentration above MEC (24 ug/mL) at steady-state.
Conclusions:
In the study, a robust population pharmacokinetic model for IMC-002 was developed. The full TMDD model well explained a nonlinear pharmacokinetic property of IMC-002, including FcRn recirculation. This model provides rationale to support a dose regimen of 20 mg/kg every 3 weeks in future clinical development studies.
References:
[1] Levy, G. “Pharmacologic target-mediated drug disposition.” Clinical pharmacology and therapeutics vol. 56,3 (1994): 248-52. doi:10.1038/clpt.1994.134
[2] Aston, Philip J et al. “Mathematical analysis of the pharmacokinetic-pharmacodynamic (PKPD) behaviour of monoclonal antibodies: predicting in vivo potency.” Journal of theoretical biology vol. 281,1 (2011): 113-21. doi:10.1016/j.jtbi.2011.04.030
Reference: PAGE 32 (2024) Abstr 10928 [www.page-meeting.org/?abstract=10928]
Poster: Drug/Disease Modelling - Oncology