  The increasing number of studies demonstrates the high potency of the
intrathecal (IT) route for the delivery of biopharmaceuticals to the central
nervous system (CNS). Our earlier data exhibited that both the infused volume
and the infusion rate can regulate the initial disposition of the administered
solute within the cerebrospinal fluid (CSF). On the other hand, fast additions
of large volumes of liquid to the CSF inevitably raise the intracranial
pressure (ICP), which may in turn lead to adverse reactions if the
physiologically delimited threshold is exceeded. While long-term biological
effects of elevated ICP (hydrocephalus) are known, the safety thresholds
pertaining to short-term ICP elevations caused by IT infusions have not yet
been characterized. This study aimed to investigate the dynamics of ICP in rats
and non-human primates (NHPs) with respect to IT infusion rates and volumes.
The data revealed that the addition of a liquid to the CSF raised the ICP in a
rate and volume-dependent manner. At low infusion rates (<0.12 ml/min in rats
and <2 ml/min in NHPs), NHPs and rats displayed similar tolerance patterns for
extended durations. Specifically, safe accommodations of such added volumes
were mainly facilitated by the accelerated pressure-dependent CSF drainage into
the blood, with ICPs stabilizing at different levels below the safety threshold
of 28+/-4 mm Hg in rats and 50+/-5 mm Hg in NHPs. High infusion rates caused
uncompensated ICP elevations rapidly exceeding the safety thresholds. Their
tolerance was species-dependent and was facilitated by the compensatory role of
the varied components of craniospinal compliance while not excluding the
possibility of other contributing factors. In conclusion, large volumes of
liquids can safely be delivered via IT routes provided that ICP is monitored as
a safety factor and cross-species physiological differences are accounted for.
