PII-090 - TRANSLATIONAL PHARMACOKINETIC-PHARMACODYNAMIC MODELING AND SIMULATION TO PREDICT EFFICACIOUS HUMAN DOSES FOR YH35324 (GI-301)

H. Hong¹, H. Lim ^1,2, M. Lee^1,2, S. Choi², S. Lee², K. Park², S. Jang³, D. Kim³, N. Yun⁴, M. Jang⁴; ¹Asan Medical Center, Seoul, Republic of Korea, ²University of Ulsan, Seoul, Republic of Korea, ³Yuhan Corporation, Seoul, Republic of Korea, ⁴GI Innovation, Seoul, Republic of Korea.

Background: YH35324 (GI-301) is a novel long-acting immunoglobulin E (IgE) Trap - Fc fusion protein under development as a therapeutic agent for various IgE-mediated allergic diseases. It has durable binding to human IgE with high affinity and inhibit mast cell degranulation potently. This modeling was conducted to characterize and predict human pharmacokinetics (PK) and pharmacodynamics (PD) of subcutaneous YH35324 using non-human primate data.

Methods: Serum YH35324 concentration and free IgE data obtained from 42 normal cynomolgus monkeys treated with single and/or once-weekly subcutaneous administrations of YH35324 were used in the PK-PD modeling. Body weight-based allometric scaling was applied to elimination rate constant, central volume of distribution, and absorption rate constant in the model to predict human PK and PD of YH35324. Simulations were conducted by different dose levels to predict the change of YH35324 and free IgE concentrations over time, and duration of free IgE suppression below target level.

Results: In simulations based on the QSS PK-PD model, a single dose more than 1 mg/kg was required to reach a free IgE level relevant to clinical benefit of below 25 ng/mL in patients with normal baseline IgE level (144 IU/mL), and more than 3 mg/kg in those with high baseline IgE level (879 IU/mL). Median clinically effective time in human were predicted to be 546.34 hours for patients with normal IgE level and 211.97 hours for those with high IgE level following 9 mg/kg of YH35324.

Conclusion: The current model predicted clear exposure-response relationship for YH35324. PK-PD model suggests that YH35324 potently and quickly decreases IgE level with a relatively long duration of effect and will help design human clinical trials for YH35324.