Table 3.
SR-PK/PD model estimation of the free AUC of PR-104A, PR-104H, and PR-104M extracted from or released into plasma by a HCT116 tumor following i.p. administration of 562 μmol/kg PR-104.
| Tumor | PR-104A | PR-104H | PR-104M | |
|---|---|---|---|---|
| Net amount extracted (−)/released (+) in the tumor microregion (pmol/mm3) | WT | −80.2 | 3.37 | 11.77 |
| sPOR#6 | −300 | 14.4 | 48.7 | |
| Net amount extracted (−)/released (+) by a 600 mm3 tumor in 1 h (nmol) | WT | −48.1 | 2.02 | 7.06 |
| sPOR#6 | −180 | 8.61 | 29.2 | |
| V D (l/kg) | – | 2.6a | 2.8b | 2.8b,c |
| CL (l/h/kg) | 5.0d | 44b | 20b,c | |
| Free AUC extracted (−)/released (+) by a 600 mm3 tumor (μM.h) | WT | −0.286 | 0.00179 | 0.0140 |
| sPOR#6 | −1.07 | 0.00759 | 0.0578 | |
| Free AUC in plasma (μM.h)c | – | 61.5 | 1.30 | 0.71 |
Using our previous PR-104 SR-PK/PD model for HCT116/WT tumors and HCT116/sPOR#6 tumors [with a 20-fold higher prodrug activation rate constant (35)], simulations were performed for a PR-104 dose of 562 μmol/kg, with inflow AUC of PR-104H and PR-104M from extra-tumor sources set to 0 to identify the flux of reduced metabolites formed in the tumor. Net transport of PR-104A, PR-104H, and PR-104M across the tumor-plasma boundary in the tumor microregion was calculated, scaled to the volume of a typical HCT116 tumor (600 mm3), and divided by the clearance (CL) for a 25 g mouse to calculate the AUC reached in plasma. The distribution volume (VD) and CL were determined in pharmacokinetic studies (see footnotes).
aEstimated for CD-1 mice following i.v. administration of 56.2 μmol/kg PR-104A (92).
bEstimated from the plasma PK of PR-104H and PR-104M measured in NIH-III nude mice after i.v. administration of 10 μmol/kg PR-104H (Figure 10).
cAssuming that VD of PR-104M is equal to VD of PR-104H.
dEstimated by non-compartmental analysis of the PR-104A plasma PK measured in NIH-III nude mice after i.p. administration of 562 μmol/kg PR-104 (35).