Table 3 Preclinical DMPK and in vitro toxicity profiling of PVTX-405

From: Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy

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

  1. 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.
  2. 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.
  3. cIV.
  4. dPO.
Back to article page