TABLE 3

Preclinical data summary and predicted human PK for AZD5069 and AZD4721

AZD5069AZD4721
CXCR2 human IL-8 binding FMAT pIC50a8.58.4
Hepatocyte CLint (µl/min per 106 cells) rat/dog/human12/11/4 (HLM CLint = 14)10/4/3 (HLM CLint = 8)
Solubility, µM19097
LogD7.4/pKa per calculated fu,inc1.7/5.8/0.81.9/5.7/0.8
PPB (% free) rat/dog per human2.4/2.3/0.590.42/0.46/0.11
Blood–plasma ratio rat/dog per human0.6/0.6/0.60.8/0.7/0.6
In Vivo PKRatDogHuman PredictionRatDogHuman Prediction
Predicted hepatic metabolic CL (ml/min per kilogram)5.45.90.361.70.800.04
Observed CL (ml/min per kilogram)4.26.52.40.50
CLrenal (ml/min per kilogram)<0.01<0.01<0.01<0.01
CLbiliary (ml/min per kilogram)0.100.10b<0.010.04
In vivo/in vitro unbound CLintc0.761.21.40.6
Vss (l/kg)0.321.10.250.190.150.11
t1/2 (h) (PO)1.0 (2.5)0.44 (2.6)7.51.3 (2.7)3.7 (8.4)30
F (%)31484582
  • a Ligand binding assay described in Connolly et al. (2013).

  • b The dog BDC study was performed after candidate drug selection. A summary of key preclinical in vitro and in vivo data are shown in Table 3. Based on IVIVE and negligible renal and biliary clearance in rat and negligible dog renal clearance (at the time of proceeding to phase 1 clinical studies, no bile duct cannulated dog PK study had been performed on AZD5069), human CL was predicted to be 0.36 ml/min per kilogram (driven by entirely hepatic metabolism), Vss was predicted to be 0.25 l/kg (based on rat and dog unbound Vss measured in non–bile duct cannulated animals), and effective half-life was consequently predicted to be 7.5 hours for AZD5069.

  • c In vivo CLint,u calculated from the well-stirred liver model (Pang and Rowland, 1977) as follows: CLint,u = CLH/fu,b × (1 − CLH/QH) and in vitro CLint,u calculated as CLint/fu,inc.