. 2016 Mar 10;18(3):589–604. doi: 10.1208/s12248-016-9889-y

Table III.

Pertinent Physico-Chemical and ADME Properties Known at the Time of AZD1283 Nomination into Clinical Development

Parameter	AZD1283
Molecular weight (Da)	470.6
logD_pH7.4	1.4
pKa of acidic ionisation centre	4.6
Binding to plasma (% free); mouse/dog/cynomolgus monkey/human	1.11/0.54/0.94/0.59^a
Solubility (μmol/L)	0.2 to 346^b
Caco-2 permeability in apical to basolateral direction, pH 6.5 to 7.4 (10⁻⁶ cm/s)	18
Hepatocyte CL_int (μL/min/10⁶ cells); mouse/rat/dog/monkey/human	ND/35/<4/ND/15
Liver microsomal CL_int (μL/min/mg); mouse/rat/dog/monkey/human	ND/285^c/<12/<12/<5
Total plasma clearance (mL/min/kg); female mouse/female Sprague-Dawley rat/Beagle dog/cynomolgus monkey	85/119/0.67/5
Hepatocyte CL_int (μL/min/10⁶ cells); mouse/rat/dog/monkey/human	ND/35/<4/ND/15
Liver microsomal CL_int (μL/min/mg); mouse/rat/dog/monkey/human	ND/285^c/<12/<12/<5
Total plasma clearance (mL/min/kg); female mouse/female Sprague-Dawley rat/Beagle dog/cynomolgus monkey	85/119/0.67/5
In vitro human blood:plasma ratio	0.63
F _oral (%); mouse/rat/dog/monkey	42/24/100/66
Calculated in vivo F _a × F _G (%); mouse/rat/dog/monkey	ND/ND/100/80^d

^aAZD1283 is stable in dog, monkey and human plasma up to 3 h at 37°C. Ester hydrolysis accounted for 43% losses observed in mouse plasma. This could be inhibited by co-incubation with 4-(2(aminoethyl)benzene sulfonyl fluoride hydrochloride. AZD1283 is chemically stable across a full pH range

^bThe aqueous solubility of AZD1283 is pH dependent and increases at pH values above its pKa. In aqueous solutions, from pH 1.1 to 8.0, the solubility ranges from 0.2 to 346 μmol/L

^cRat microsomal CL_int is high in the presence and absence of NADPH

^dThe in vivo F _a × F _G was calculated from IV and oral PK data using the indirect method according to equation F _oral/F _H = F _a × F _G. The LBF values used at the time for calculation of F _h in mouse, rat, dog, monkey and human were 152, 80, 33, 44 and 21 mL/min/kg, respectively