Cross-species prediction of CL

NCE 14MouseRatMonkeyDogHuman
 CLh int, u (µl/min/million cells)763354237.8
 CLb int, u (μl/min/g)4.51832.93.910.2
 Total scaled CLb (ml/min/kg)9761932713
 Observed CLb (ml/min/kg)76714542NA
PF-06651600 (NCE12)
 Plasma protein binding (fup)0.320.530.810.660.86
 Hepatocyte CLint, u (µl/min/million cells)53147.62.12.8b
 Blood CLint, u (μl/min/g)5.610413.70.56c
 Total scaled CLb (ml/min/kg)8653103125.6
 Observed CLb (ml/min/kg)4853428.67.3d
  • NA, not available.

  • a Estimated value due to high blood instability.

  • b Relay hepatocyte stability model required (Di et al., 2012).

  • c rhGST P1-1 intrinsic CLint (CLint, rhGSTP1-1) required due to low in vitro CLb int, u using a linear regression relationship developed in human for a set of novel JAK3 acrylamide covalent inhibitors: CLb int, u (μL/min/g) = 31.5 CLint, rhGSTP1-1 − 0.39 (Fig. 4).

  • d Clinical CL/F based on a daily 200-mg dose given by mouth (unpublished data); n = 2 for fup, BPR, hepatocyte and blood CLint, u, and in vivo CLb assessments.