Pharmacokinetic analysis of carboplatin and fluorescein brain permanence following ultrasound-based blood-brain barrier opening

BackgroundThe 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 permanence upon short-lived BBB opening is unknown. We compared the parenchymal permanence of temozolomide, carboplatin, and fluorescein, and investigated the effect of LIPU/MB on the concentration of carboplatin and fluorescein. MethodsWe 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 non-sonicated brain and measured drug levels over 24 hours. Published data from a microdialysis study of temozolomide without LIPU/MB were used for comparison. ResultsLIPU/MB led to sustained elevated parenchymal drug concentrations, achieving 3.1-fold increase in brain-to-plasma AUC for carboplatin and fluorescein (P = 0.03). Compared to non-sonicated brain, sonicated brain had higher concentrations of carboplatin for 11 hours, and fluorescein for 5 hours. Drug levels in the sonicated brain exceeded their plasma concentrations at 21 hours and 7 hours, for carboplatin and fluorescein, respectively. In non-sonicated brain, drug half-life was longest for fluorescein (13.6 {+/-} 11.0 hours), followed by carboplatin (5.1 {+/-} 1.9 hours) and temozolomide (2.9 {+/-} 1.6 hours). Sonication did not affect parenchymal drug half-life. ConclusionFollowing LIPU/MB, BBB-impermeable drugs exhibit sustained elevated parenchymal concentrations surpassing their plasma levels, highlighting the bi-directional 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.