Table 3.
Preclinical DMPK and in vitro toxicity profiling of PVTX-405
| solubility (µM) | 319.4 (SGF), 318.5 (SIF), 283.7 (FeSSIF), 304.8 (FaSSIF) |
| liver microsomal stability, T1/2 (min) | >120 (human), 36 (monkey), >120 (rat), >120 (mouse) |
| plasma stability, T1/2 (min) | >240 (human), >240 (monkey), >240 (rat), >240 (mouse) |
| Caco-2 permeability | Papp = 5.9 × 10−6 cm/s, efflux ratio = 4.4 |
| plasma protein binding (%) | 91.5 (human), 94.3 (monkey), 91.2 (rat), 93.4 (mouse) |
| CYP inhibition, IC50 (µM) | >10 (3A4, 1A2, 2B6, 2C8, 2C19,2D6) |
| mouse PK profileb | Vssc = 2.7 L/kg, Clc = 19 mL/min/kg, T1/2d = 3.8 h, Cmaxd = 600 ng/mL, AUC d = 1997 (h*ng/mL), F = 76% |
| rat PK profileb | Vssc = 2.9 L/kg, Clc = 20 mL/min/kg, T1/2 d = 2.6 h, Cmaxd = 417 ng/mL, AUCd = 2765 (h*ng/mL), F = 118% |
| monkey PK profileb | Vssc = 8.1 L/kg, Clc = 19 mL/min/kg, T1/2d = 10 h, Cmaxd = 111 ng/mL, AUCd = 1289 (h*ng/mL), F = 50% |
| PXR activation | no activation |
| reactive metabolites | not detected using GSH as trapping agent |
| hepG2 cytotoxicity | IC50 > 50 µM |
| aldehyde oxidase substrate | negative |
| BSEP inhibition | IC50 > 30 µM |
| mini-Ames toxicity | negative |
aSGF simulated gastric fluid; SIF simulated intestinal fluid; FeSSIF fasted state simulated intestinal fluid; FaSSIF fed state simulated intestinal fluid; IV intravenous administration; PO oral administration; T1/2 elimination half-life; AUC area-under-the-curve; Vss volume of distribution at steady state; Cl clearance; Cmax maximum drug concentration; F oral bioavailability; FXR pregnane X receptor; GSH Glutathione; BSEP bile salt export pump. All the data are presented as mean of at least two biological replicates. Source data are provided as a Source Data file.
bPK studies were carried out at the IV dose of 1 mg/kg and PO dose of 3 mg/kg using 5% DMSO + 10% Solutol + 85% Saline as the dosing vehicle.
cIV.
dPO.