DSAI-04 FOCUSED ULTRASOUND-ENHANCED DRUG DELIVERY TO THE HUMAN BRAIN AND BRAIN TUMORS: MECHANISTIC AND QUANTITATIVE INSIGHTS FROM PHYSIOLOGICALLY BASED CNS PHARMACOKINETIC MODELING

Abstract

Focused ultrasound (FUS) combined with systemically administered microbubbles enables transient disruption of the blood–brain barrier (BBB), offering a promising strategy to enhance central nervous system (CNS) delivery of therapeutics. However, limited quantitative understanding of how FUS-induced BBB opening modulates CNS pharmacokinetics (PK) hinders its rational clinical translation. This study developed a mechanistic, physiologically based pharmacokinetic (PBPK) modeling framework to characterize CNS PK and identify key determinants governing drug delivery to CNS tumors. A 9-compartment CNS PBPK model was developed that captured key anatomical and pathophysiological features of the human CNS and brain tumors. The model included three tumor compartments, representing infiltrative tumor with intact BBB, infiltrative tumor with FUS-induced BBB opening, and bulk tumor with constitutively disrupted BBB. FUS-disrupted BBB was modeled as time-dependent increases in paracellular permeability with defined BBB opening onset and duration. The model was applied to four therapeutic drugs, including the small-molecule temozolomide, HER2 monoclonal antibody trastuzumab, and antibody–drug conjugates trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). Simulations suggest that FUS-induced BBB opening produces distinct, drug-specific effects on CNS tumor PK, driven by BBB transport kinetics and systemic pharmacokinetics. For antibodies and antibody–drug conjugates, which exhibit intrinsically low BBB permeability and prolonged systemic exposure, CNS penetration is predominantly BBB permeability-limited and benefits from sufficiently large and sustained BBB disruption. In contrast, for rapidly cleared small molecules such as temozolomide, CNS penetration is primarily systemic exposure-limited and requires precise temporal alignment between BBB opening onset and drug administration time. In conclusion, the 9-CNS PBPK model provides a mechanistic computational framework linking the efficiency of FUS-enhanced CNS drug delivery to drug properties, systemic pharmacokinetics, and BBB transport kinetics, which enables tailoring FUS parameters for optimal BBB opening onset, duration, and magnitude to maximize therapeutic delivery to brain tumors while maintaining safety.