TABLE 2

Cross-species prediction of CL

Parameters	Species
NCE 14	Mouse	Rat	Monkey	Dog	Human
fup	0.54	0.36	0.62	0.69	0.60
BPR	1.3	1.5	1.7	1.4	1.7
CLh int, u (µl/min/million cells)	76	33	54	23	7.8
CLb int, u (μl/min/g)	4.5	18	32.9	3.9	10.2
Total scaled CLb (ml/min/kg)	97	61	93	27	13
Observed CLb (ml/min/kg)	76	71	45	42	NA
PF-06651600 (NCE12)
Plasma protein binding (fup)	0.32	0.53	0.81	0.66	0.86
BPR	0.94	1.3	1.5^{^a}	1.6	1.6
Hepatocyte CLint, u (µl/min/million cells)	53	14	7.6	2.1	2.8^b
Blood CLint, u (μl/min/g)	5.6	10	41	3.7	0.56^c
Total scaled CLb (ml/min/kg)	86	53	103	12	5.6
Observed CLb (ml/min/kg)	48	53	42	8.6	7.3^{^d}

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↵^d Clinical CL/F based on a daily 200-mg dose given by mouth (unpublished data); n = 2 for fu_p, BPR, hepatocyte and blood CLint, u, and in vivo CLb assessments.