Large-Volume Intrathecal Administrations: Impact on CSF Pressure and Safety Implications

Area of Science:

• Pharmacology and Toxicology
• Neuroscience
• Biomedical Engineering

Background:

• Intrathecal (IT) drug delivery to the central nervous system (CNS) is increasingly potent.
• Infused volume and rate impact initial cerebrospinal fluid (CSF) disposition.
• Elevated intracranial pressure (ICP) from IT administration can cause adverse effects; short-term safety thresholds are unknown.

Purpose of the Study:

• To investigate intracranial pressure (ICP) dynamics in rats and non-human primates (NHPs) related to IT infusion rates and volumes.
• To estimate and analyze safety regimes across species for translational large-volume IT therapies.

Main Methods:

• Monitored ICP in rats and NHPs during IT infusions of varying rates and volumes.
• Analyzed ICP responses in relation to infusion parameters and species-specific physiological differences.
• Assessed safety thresholds based on ICP stabilization and tolerance durations.

Main Results:

• ICP elevation was dependent on infusion rate and volume.
• At low infusion rates (<0.12 ml/min in rats, <2 ml/min in NHPs), ICP stabilized below safety thresholds (28 ± 4 mm Hg in rats, 50 ± 5 mm Hg in NHPs) due to enhanced CSF drainage.
• High infusion rates caused rapid, uncompensated ICP elevations exceeding safety thresholds, with tolerance varying by species and influenced by craniospinal compliance.

Conclusions:

• Large-volume IT therapies are feasible if ICP is monitored.
• Safe IT administration requires accounting for cross-species physiological differences.
• Controlled infusion rates are key to managing ICP and preventing adverse events.