Preclinical characterization of the absorption and disposition of the brain penetrant PI3K/mTOR inhibitor paxalisib and prediction of its pharmacokinetics and efficacy in human

Abstract

1. Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults. Available treatments have not markedly improved patient survival in the last twenty years. However, genomic investigations have showed that the PI3K pathway is frequently altered in this glioma, making it a potential therapeutic target.

2. Paxalisib is a brain penetrant PI3K/mTOR inhibitor (mouse Kp,uu 0.31) specifically developed for the treatment of GBM. We characterised the preclinical pharmacokinetics and efficacy of paxalisib and predicted its pharmacokinetics and efficacious dose in humans.

3. Plasma protein binding of paxalisib was low, with the fraction unbound ranging from 0.25 to 0.43 across species. The hepatic clearance of paxalisib was predicted to be low in mice, rats, dogs and humans, and high in monkeys, from hepatocytes incubations. The plasma clearance was low in mice, moderate in rats and high in dogs and monkeys. Oral bioavailability ranged from 6% in monkeys to 76% in rats.

4. The parameters estimated from the pharmacokinetic/pharmacodynamic modelling of the efficacy in the subcutaneous U87 xenograft model combined with the human pharmacokinetics profile predicted by PBPK modelling suggested that a dose of 56 mg may be efficacious in humans.

   Paxalisib is currently tested in Phase III clinical trials.

Keywords:

• PI3K
• PI3K inhibitor
• glioblastoma
• blood-brain barrier
• cerebrospinal fluid
• PK/PD modelling
• PB/PK modelling
• pharmacokinetics

Author contributions

Participated in research design: Salphati, Pang, Alicke, Pang, Plise, Cheong, Olivero, Sampath; Conducted experiments: Alicke, Plise, Cheong, Jaochico, Wong, Zhang; Contributed new reagents or analytical tools: Zhang, Plise, Cheong, Jaochico; Performed data analysis: Salphati, Pang, Alicke, Sampath, Wong, Zhang; Wrote or contributed to the writing of the manuscript: Salphati, Pang, Alicke, Wong.

Disclosure statement

The authors were employees and/or shareholders of Roche at the time of the studies.

Data availability statement

The authors declare that all the data supporting the findings of this study are available within the paper.

Additional information

Funding

No specific funding was received for this work.