Preclinical Modeling of Navtemadlin Pharmacokinetics, Pharmacodynamics, and Efficacy in IDH-Wild-type Glioblastoma.

ABSTRACT:

Purpose

Navtemadlin is a potent small-molecule inhibitor of MDM2, which has completed a phase 0 window-of-opportunity study in glioblastoma (GBM). To optimally interpret the clinical data, a detailed analysis of navtemadlin pharmacokinetics (PK), pharmacodynamics, and efficacy was performed in GBM patient-derived xenografts (PDX).

Experimental design

Response to navtemadlin was characterized in vitro and in vivo in GBM PDXs with and without MDM2 amplification. Efficacy in vivo was integrated with measured plasma and intra-tumoral drug levels to develop a translational PK/efficacy model comparing exposure effective in PDX to exposure achieved in phase 0 patient samples.

Results

In vitro, navtemadlin showed robust on-target activity in TP53-wild-type GBM. In vivo effica

SUBMITTER: Vaubel RA 

PROVIDER: S-EPMC12402800 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature