TABLE 7

Biochemical and physicochemical data for PBPK model development

Biochemical data are means of at least triplicate experiments.

Parameter	ACT-541468	ACT-605143	ACT-658090
logD	3.8	4.0	4.3
pK_a	4.2	4.0	4.2
Molecular weight (g/mol)	451	449	490
Solubility FaSSIF (μg/ml)^a^,^f	79	76	196^d
Solubility FeSSIF (μg/ml)^b	256	83	653^d
Solubility PB (μg/ml)^c	14	18^e	32^d
f_{u,OX2 assay}	0.79	0.80	0.69
f_u,brain	0.010	0.008	0.007
f_u,mic	0.41	0.34	0.29
Permeability (A-to-B, 10⁻⁶ cm/sec)	22.6	15.4	34.3
CL_int (μl/min/mg, rat)	990	835	988
f_u,plasma (rat)	0.028	0.012	0.009
Blood/plasma ratio (rat)	2.1	0.9	0.8
CL_int (μl/min/mg, dog)	235	212	89
f_u,plasma (dog)	0.024	0.012	0.008
Blood/plasma ratio (dog)	0.7	0.5	0.6
CL_int (μl/min/mg, human)	138	149	69
f_u,plasma (human)	0.0013	0.0004	0.0010
Blood/plasma ratio (human)	0.5	0.7	0.7

f_u,brain, fraction unbound in the brain; f_u,gut, fraction unbound in the gut; f_u,mic, fraction unbound in liver microsomes; f_{u,OX2 assay}, fraction unbound in OX₂ binding assay; f_u,plasma, fraction unbound in plasma.
↵^a FaSSIF, simulated intestinal fluid at fasted state, pH 6.5 and 37°C.
↵^b FeSSIF, simulated intestinal fluid at fed state, pH 5.0 and 37°C.
↵^c PB, phosphate buffer, pH 7.0–7.4, 25°C.
↵^d Noncrystalline material.
↵^e At 37°C.
↵^f Data of hydrochloride salt.