Table I.
DMPK Properties for AZ12470164 Prior to its Nomination into Clinical Development and Following FIH Phase I Trials
| Parameter | AZ12470164 |
|---|---|
| Molecular weight (Da) | 399.4 |
| logD7.4 | >3 |
| Binding to plasma (% free) | <3 across mouse, rat, dog and human |
| Solubility at pH7.4 (μmol/L) | 46 |
| Caco-2 P app in apical to basolateral direction, pH 6.5 to 7.4 (10−6 cm/s) | 18 to 27, no evidence of efflux |
| Hepatocyte CLint (μL/min/106 cells); mouse/rat/dog | 7/43/<1 |
| Human liver microsomal CLint (μL/min/mg protein) | 18 |
| Total plasma clearance (mL/min/kg); CD-1 mouse/Han Wistar rat/Beagle dog | 125/22/8.6 |
| F oral (%); mouse/rat/dog | 56/14/44 to ∼100a |
| Calculated in vivo F a × F G (%); mouse/rat/dog | >100/20/50 to ∼100c |
| Predicted human F a (%) | 60 |
| Predicted MAD (mg) | 800 |
| Predicted human clearance (mL/min/kg) | 5.6 |
| Predicted human F oral (%) | 46 |
| Predicted biologically effective dose from once daily schedule (mg) | 154 |
| CL/F oral (L/h) ± Stdev | 2790 ± 2960b |
| Vz/F oral (L) ± Stdev | 12,400 ± 862b |
| Revised biologically effective dose for once daily schedule (mg) | >3000 |
Metabolism studies in hepatocytes from mouse, rat, dog and human revealed that AZ12470164 underwent many oxidative reactions as well as direct glucuronidation. No information was available on the phase II enzyme isoforms responsible for metabolism of AZ12470164, but CYP2C19, and to a lesser degree CYP3A4, mediated the phase I oxidative processes
ND not determined
aThe F oral was approximately 50% from low oral doses, but was complete at 100 mg using the formulation identified for the first in human studies. Phase I clinical PK data for a patient cohort receiving 80 mg orally
bThe clearance and terminal volume of distribution (V z) are reported as CL/F oral and V z/F oral as they are derived from oral dosing
cThe in vivo F a × F G was calculated from IV and oral PK data using the indirect method given by F oral/F H = F a × F G