DDEL-10. RETROSPECTIVE REVIEW OF INTRA-CSF DRUG DELIVERY: SAFETY AND DRUG DISTRIBUTION PROFILES OF INTRACEREBROVENTRICULAR (ICV), LUMBAR INTRATHECAL (LIT), AND INTRA-CISTERNA MAGNA (ICM) INJECTIONS

Abstract

Abstract INTRODUCTION The blood-brain barrier and blood-CSF barrier limit the uptake of CNS-targeted therapeutics. Given this limitation, intra-cerebrospinal fluid (CSF) drug delivery can be utilized. Here we review and compare thesafety and drug distribution of the different intra-CSF drug delivery methods. METHODS A retrospective literature review of the three most common CSF access methods (intracerebroventricular (ICV), lumbar intrathecal (LIT), and intra-cisterna magna (ICM)) was performed. The search consisted of human clinical trials published on PubMed from 2000 to present, with the following terms: intracerebroventricular/intraventricular/ICV, intrathecal/IT, cisterna magna/ICM/IT-CM, drug delivery, drug administration, and CSF. RESULTS The search yielded 34 ICV, 72 LIT, and 6 ICM studies. To investigate the safety and drug concentration profiles of each delivery method, we excluded studies reporting drug adverse events (AEs) rather than AEs related to the specific drug delivery method, leaving 21 ICV, 30 LIT, and 1 ICM studies, all of which spanned oncology and non-oncology treatment studies. ICV-specific safety was addressed in 10 ICV studies, with infection (N=6) and device malfunction (N=2) being among the most frequently mentioned device/procedure-associated AEs. LIT-specific safety was provided in 17 studies, with post-procedural headache (N=9), infection (N=5), and pain (N=5) being among the most mentioned AEs. For drug distribution, 42.9% (N=9) of ICV studies concluded that ICV delivery achieved sufficient drug exposure in the CNS for a meaningful therapeutic benefit, with drug concentrations reaching minimum effective doses and/or achieving high therapeutic indices. The single ICM study with infusion of bupivacaine for pain management did not analyze safety or drug distribution. Meanwhile, 30.0% (N=9) of LIT studies reached the same conclusion or achieved concentrations consistent with predicted values. CONCLUSION The safety profiles of both ICV and LIT injections are acceptable, showing mostly mild-to-moderate device/procedure-associated AEs. Additionally, ICV achieves therapeutic goals more consistently than the other intra-CSF delivery methods.