D3S-003（一种口服生物利用度高的双状态KRAS G12D抑制剂）的首次人体临床药代动力学预测

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.