ADME & Toxicology (Phase I Enabling)

ADME Profile

1. 99% plasma protein binding
2. Moderate intrinsic clearance (human liver microsomes: ~3.3 mL/min/g)
3. Minimal CYP450 inhibition
4. Poor intestinal permeability → supports IV strategy
5. Not a significant P-gp substrate

GLP Toxicology

1. 29-day IV toxicology studies:
   1. Rat NOAEL: 1 mg/kg/day
      1. Cmax ~143 ng/mL
      2. AUC ~174 ng·h/mL
   2. Dog NOAEL: 33 mg/kg/dose
2. Toxicities:
   1. Dose-related
   2. Primarily reversible renal and infusion-site effects
3. Data supported a conservative human starting dose of 10 mg

From a buyer’s perspective, this reflects disciplined risk management at FIH entry.