Translational pharmacokinetic-pharmacodynamic modeling and simulation to predict efficacious human doses for YH35324 (GI-301)
Kwan Cheol Pak (1,2), Seung Chan Choi (1,2), Sang Min Lee (1,2), Moon Hee Lee (1,2), Kyung Ran Mun (1,2), Seong Bok Jang (3), Dong Kyun Kim (3), Nari Yun (4), Myoung Ho Jang (4), Hyeong-Seok Lim (1,2)
(1) Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, (2) Department of Medical Science and Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, (3) Yuhan Corporation, Seoul, Republic of Korea, (4) GI Innovation, Inc., Seoul, Republic of Korea
Objectives: YH35324 (GI-301) is a novel long-acting immunoglobulin E (IgE) Trap-Fc fusion protein under clinical development, which comprises the human FcεRI extracellular domain fused to a human IgD/IgG4 hybrid Fc region. YH35324 has more durable binding to human IgE with 75-fold higher affinity and elicits 52-fold more potent inhibition of mast cell degranulation than omalizumab. Given these in vitro characteristics, YH35324 is considered to be superior to omalizumab in binding free IgE and is a more potent inhibitor of mast cell degranulation. The current model was constructed to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of YH35324 for non-human primates and to predict the PK and PD profile of various doses of YH35324 when subcutaneously injected in humans.
The major purposes of this study were followed as:
- To develop a model describing PK and PD profile in non-human primates following subcutaneous injection of YH35324,
- To predict the PK and PD profiles of human taken various doses of YH35324 based on PK-PD model constructed using non-human primates,
- To simulate the exposure-response relationships of YH35324 in human
Methods: Serum YH35324 concentration and free IgE data obtained from 42 normal cynomolgus monkeys treated with single or once-weekly subcutaneous administrations of YH35324 for 2 weeks or 13 weeks were used to construct the PK-PD model for non-human primates. Various linear and non-linear structural models were assessed using a graphical assessment of optimum fit capabilities and statistical significance criteria. Significant covariates were statistically assessed using a likelihood ratio test. The predictability of the PK-PD model was evaluated using visual predictive check (VPC) plots [1].
Body weight-based allometric scaling was applied to elimination rate constant, central volume of distribution, and absorption rate constant in this model to predict human PK and PD of YH35324 based on a previous report [2].
To compare the effect of YH35324 on free IgE suppression in patients with normal or high baseline IgE level, simulations included two groups: those with normal baseline IgE level (144 IU/mL on average) and those with high baseline level (879 IU/mL on average, >700 IU/mL) [3]. Simulations were conducted to predict PK and PD profiles, and duration of YH35324 effect to suppress free IgE concentration below target level of 25 ng/ml which corresponds to 10.42 IU/mL over a dose range of 0.1 to 9.0 mg/kg.
Modeling and simulation in this study were performed using NONMEM® version 7.4.3 and gfortran compiler (ICON Development Solutions, Ellicott City, MD, USA) [4], and data were handled and plotted using R version 3.5.3 [5].
Results: The conventional quasi-steady state (QSS) model, which explains the binding relation of one YH35324 molecule to one IgE molecule, described the PK and PD data of non-human primates well. However, the current model showed under-prediction for the PK data around maximum concentrations. Basic goodness-of-fit plots, conditional weighted residual plots, and VPC plots suggested that the model predicts the observed concentrations reasonably well. Simulations were conducted to predict human PK regardless of sex, as sex was found to be a significant covariate but had minimal impact on exposure in non-human primate simulations.
In simulations for humans weighing 70 kg based on the QSS model, a single dose of more than 1 mg/kg was required to reach the median free IgE level below 25 ng/mL (target level) in patients with a normal baseline IgE level (144 IU/mL) and more than 3 mg/kg in those with a high baseline IgE level (879 IU/mL). The median clinically effective duration maintaining the free IgE level below 25 ng/mL were predicted to be 546.34 hours for the patients with normal IgE level and 211.97 hours for those with high IgE level following 9 mg/kg of YH35324. A clear exposure-response relationship was observed, and the duration to sustain free IgE below the target level increased with increasing dose of YH35324.
Conclusions: The current model described the PK and PD of YH35324 well in non-human primates and predicted human PK and PD by simulations. This PK-PD model suggests that YH35324 has a potent and rapid effect in decreasing IgE levels with a relatively long duration of pharmacological effect. Although the predictions seem to be under-predictive, the model provides useful information for PK-PD characteristics of YH35324, which will help design a first-in-human clinical trial for YH35324.
References:
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