Table 4. In Vitro/In Vivo Profile of Compound 27a.
27: MW = 557, TPSA = 112, log D7.4 = 3.8 | |
---|---|
human LM Clint/Hep Clint | 7.2/41 |
rat LM Clint/Hep Clint | 43/33 |
dog LM Clint/Hep Clint | 20/21 |
cyno LM Clint/Hep Clint | 55/80 |
cyno IV PK Cl (mL min–1 kg–1)b (Clu)c | 31.8 (611) |
cyno IV PK t1/2 (h) | 2.9 |
LM Clint represents intrinsic clearance obtained from isolated microsomes (units = μL/min/mg) with NADPH, and Hep Clint represents intrinsic clearance obtained from isolated hepatocyte cells (units = μL/min/million cells).
Cynomolgus monkey, 0.5 mg/kg IV and 5 mg/kg PO dose. For IV and PO dosing, 27 was formulated in 5% DMSO + 5% kolliphor HS 15 + 90% saline vehicle. Cl: plasma clearance after administration of single IV bolus dose.
Clu: unbound in vivo clearance (in vivo cyno clearance/free fraction in cyno), free fraction calculated from plasma protein binding determined by ultracentrifugation method.