Physical chemistry and blood binding | |
Mol. wt, (g/mol) | 349.44 | |
LogP | 2.643 | Calculated logP (inhouse) |
Compound type | Diprotic acid | |
pKa | 8.4 and 9 | Measured (internal data) |
Blood-to-plasma ratio | 1.4 | Measured (internal data) |
fu,plasma | 0.104 | Measured (internal data) |
Absorption | | |
Model used | First order | |
fa (CV%) | 1 (30%, default) | Clive et al. (2012) |
ka,(per h) (CV%) | 0.32 (30%, default) | Savelieva et al. (2015) |
fugut | 1 | Simcyp default and to minimize Fg value |
Qgut, lit(CV%) | 2.8 (30%, default) | Manually optimized for fit of clinical PK and DDI data |
Distribution | | |
Model used | Minimal PBPK | |
kin,(per h) | 1.42 | Savelieva et al. (2015) |
kout(per h) | 0.04 | Savelieva et al. (2015) |
Vsac, l/kg | 10.5 | Manually optimized for fit of clinical PK data |
Vss, l/kg (CV%) | 13 (15%) | Estimate |
Elimination | | |
Model used | Retrograde modela | |
CLint CYP3A4, µl/min per pmol P450 | 0.3071 | Based on relative P450 contributions Determined in vitro |
CLint CYP2D6, µl/min per pmol P450 | 1.578 |
CLint CYP2C19, µl/min per pmol P450 | 0.2254 |
Additional HLM CL, µl/min per mg protein (CV%) | 35.96 (30%, default) | Estimate of non-P450 mediated CL |
CLR, l/h (CV%) | 3.57 (30%, default) | Clive et al. (2012) |
Interaction | | |
Ki, CYP2C19 (µM) | 17.5b | Measured |
Ki, CYP2D6 (µM) | 0.167 | Measured |
Ki, CYP3A4 (µM) | 7.5b | Measured |
kinact (per h) | 1.37 ± 0.187 | Measured |
KI (µM) | 12.0 ± 4.47 | Measured |