Pharmacokinetic Analysis of Carboplatin and Fluorescein Brain Retention following Ultrasound-Based Blood-Brain Barrier Opening.

Abstract

Purpose: The blood-brain barrier (BBB) impedes the passage of most circulating drugs into the brain. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) transiently opens the BBB, improving parenchymal drug penetration. Parenchymal drug retention following short-lived BBB opening is unknown. We investigated the effect of LIPU/MB on the concentration of carboplatin and fluorescein over time and compared the parenchymal retention of temozolomide (TMZ), carboplatin, and fluorescein in the nonsonicated brain.

Experimental design: We analyzed four patients who underwent intraoperative LIPU/MB with intravenous administration of carboplatin and fluorescein in the NCT04528680 clinical trial. Microdialysis catheters were implanted into sonicated and nonsonicated brain regions, and drug levels were measured over 24 hours. Published microdialysis data of TMZ without LIPU/MB were used for comparison.

Results: LIPU/MB led to sustained elevated parenchymal drug concentrations, achieving a 3.1-fold increase in brain-to-plasma AUC for carboplatin and fluorescein (P = 0.03). In the nonsonicated brain, TMZ concentrations remained below their plasma levels, as parenchymal drug clearance mirrored plasma clearance. In contrast, BBB-impermeable drugs such as carboplatin and fluorescein exhibited delayed parenchymal clearance, resulting in higher brain than plasma drug levels over time. Parenchymal drug clearance of carboplatin and fluorescein was not affected by sonication.

Conclusions: Following LIPU/MB, BBB-impermeable drugs exhibit sustained elevated parenchymal concentrations surpassing their plasma levels, highlighting the bidirectional restriction of drug passage by the BBB. Future studies are warranted to explore drug trapping and the efficacy of sustained exposure to cytotoxic drugs for the treatment of brain-infiltrating tumors.