Abstract 1831: First-in-human clinical pharmacokinetic prediction of D3S-003, an orally bioavailable dual-state KRAS G12D inhibitor.

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Abstract Background: D3S-003 is a potent and selective KRAS G12D inhibitor that engages both GDP-bound (OFF) and GTP-bound (ON) KRAS G12D and demonstrates broad preclinical antitumor activity. To support rational first-in-human (FIH) dose selection, translational pharmacokinetic (PK) modeling and allometric scaling were applied to predict human PK characteristics from multi-species data. Methods: PK data from mouse, rat, and dog were analyzed using two-compartment models with first-order absorption and linear elimination. Allometric scaling of clearance (CL), central and peripheral distribution volumes (Vc, Vp), and intercompartmental clearance (Q) was performed to derive human PK parameters. Absorption rate constant (Ka) and bioavailability (F) were explored over a broad range to capture interspecies variability, and human simulations were conducted for oral doses of 60-1200 mg once daily. Exposure metrics (Cmax, AUC0-24, Cmin, Cavg) were predicted for both single- and multiple-dose regimens to assess dose proportionality and steady-state PK. Results: Allometric extrapolation yielded predicted human parameters of CL = 0.869 L/h/kg, Vc = 2.151 L/kg, Q = 0.693 L/h/kg, and Vp = 16.664 L/kg. Results shown here reflect simulations using mid-range absorption and bioavailability assumptions. Simulated profiles indicated rapid absorption (Tmax ≈ 1-2 h) and biexponential decline consistent with moderate distribution and linear clearance. Across 60-1200 mg QD, predicted Cmax rose from ∼26 to ∼520 ng/mL and AUC0-24 from ∼91 to ∼1824 ng·h/mL after a single dose. At steady state (τ = 24 h), Cmin and Cavg ranged ∼2-46 ng/mL and ∼6-127 ng/mL with minimal accumulation (∼1.7-fold). Simulated exposures at clinically feasible doses exceeded unbound exposure level (Cave of ∼2.3nM) associated with complete tumor regression in preclinical models, suggesting a high likelihood of achieving pharmacologically active concentrations and early clinical responses during dose escalation. Conclusions: A translational PK and allometric-scaling strategy successfully predicted human PK for D3S-003. Simulations under mid-range absorption conditions demonstrated linear exposure and favorable oral PK, supporting model-informed dose selection for the planned FIH study. Ongoing integration of clinical data will refine dose-exposure-response relationships and guide dose optimization in later-phase clinical development. Citation Format: Shaonan Wang, Zhiqiang Zheng, Jing Zhang, Tienan Wang, Xin Xiong, Hui Wang, Zhijian Chen. First-in-human clinical pharmacokinetic prediction of D3S-003, an orally bioavailable dual-state KRAS G12D inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1831.

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