Abstract
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). This disposition is one of key factors in defining the subsequent transport of the solute to its intended target. On the other hand, fast additions of large volumes of liquid to the CSF inevitably raise the CSF pressure [a.k.a. 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 administrations 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 safety regimes were estimated and analyzed across species to facilitate the development of translational large-volume IT therapies. 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. Specifically, safe accommodations of such added volumes were mainly facilitated by the accelerated pressure-dependent CSF drainage into the blood, with I stabilizing at different levels below the safety threshold of 28 ± 4 mm Hg in rats and 50 ± 5 mm Hg in NHPs. These ICPs were safely tolerated for extended durations (of at least 2–25 min). High infusion rates (including boluses) caused uncompensated exponential 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.
Highlights
Considering prior advances in intracranial pressure (ICP) research obtained primarily from trauma and hydrocephalus patients, this study aims to establish a method of ICP monitoring for characterizing disbalances in the cerebrospinal fluid (CSF) pressure caused by various modes of IT administrations
An IT administration normally results in ICP elevations due to the increased volume in the subarachnoid space
We induced in rats (n = 4) progressively increased CSF pressures and monitored the changes in the key ICP parameters: mean ICP, ICP amplitude (P1), and spectral characteristics of the ICP waveform’s major components
Summary
The IT drug delivery route is of increasing interest due to the absence of continuous barriers between the cerebrospinal fluid (CSF) and central nervous system (CNS) (Davson et al, 1987), which makes the fraction of CSF-borne compounds delivered to the brain from the CSF through perivascular channels (Wagner et al, 1974; Rennels et al, 1985; Durcanova et al, 2019) pharmacologically significant (Kakkis et al, 2004; Ishigaki et al, 2007; Tsai et al, 2007; Calias et al, 2011; Papisov et al, 2012a,b) This is especially important for macromolecules, including biopharmaceuticals, for which the access to CNS from the systemic circulation is hindered due to large molecular size and the presence of several vascular barriers (blood-brain, blood-arachnoid, and blood-CSF) (Begley, 2004; Pardridge, 2005). Both methods are relatively simple, well developed, and suitable for biopharmaceuticals, such as gene vectors, intended for single injections or multiple injections given at a large interval (several months)
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