DDEL-15. PHARMACOKINETIC ANALYSIS OF CARBOPLATIN AND FLUORESCEIN BRAIN PENETRATION AND PERMANENCE FOLLOWING ULTRASOUND-BASED BLOOD-BRAIN BARRIER OPENING ON GLIOBLASTOMA CLINICAL TRIAL

Abstract 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 drug delivery to the brain. The implication of this transient BBB opening on parenchymal drug permanence is unknown. We compared the parenchymal levels and permanence/retention of temozolomide, carboplatin, and fluorescein, and investigated in a clinical trial (NCT04528680) the effect of LIPU/MB on the permanence of carboplatin and fluorescein in the human brain. Four patients underwent intraoperative LIPU/MB (SonoCloud-9, Carthera) with intravenous carboplatin and fluorescein infusion. Microdialysis catheters were implanted into sonicated and non-sonicated brain for continuous drug measurement over 24 hours. Published data from a microdialysis study of temozolomide were used for comparison. Temozolomide and carboplatin exhibited similar brain-to-plasma AUC ratios (17.8 ± 13.3%; 16.3 ± 8.2%, respectively) which were higher than that of fluorescein (10.4 ± 6.9%). Parenchymal half-life was the longest for fluorescein (13.6 ± 11.0 hours), followed by carboplatin (5.1 ± 1.9 hours) and temozolomide (2.9 ± 1.6 hours). LIPU/MB led to sustained elevated parenchymal drug concentrations, achieving a 3.1-fold increase in AUC for both carboplatin (P = 0.02), and fluorescein (P = 0.04), and higher parenchymal than systemic drug levels starting at 21 hours and 7 hours for these drugs respectively (P < 0.05), timepoints where these drugs had mostly cleared from the plasma. Fluorescein exhibits prolonged permanence in the brain parenchyma and may be “trapped” by the BBB. In the context of transient BBB opening by LIPU/MB, parenchymal carboplatin and fluorescein concentrations remain elevated over time, supporting the notion that the BBB exhibits a bi-directional restriction of drug passage. Future studies are warranted to explore the efficacy of drug trapping to achieve prolonged/sustained exposure of cytotoxic drugs for brain tumor therapy.