The Effect of Pulsatile Flow on Intrathecal Drug Delivery in the Spinal Canal

PurposePredicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human brain disposition.MethodsA mathematical model consisting of several physiological brain compartments in the rat was developed using rich concentration-time profiles from nine structurally diverse drugs in plasma, brain extracellular fluid, and two cerebrospinal fluid compartments. The effect of active drug transporters was also accounted for. Subsequently, the model was translated to predict human concentration-time profiles for acetaminophen and morphine, by scaling or replacing system- and drug-specific parameters in the model.ResultsA common model structure was identified that adequately described the rat pharmacokinetic profiles for each of the nine drugs across brain compartments, with good precision of structural model parameters (relative standard error <37.5%). The model predicted the human concentration-time profiles in different brain compartments well (symmetric mean absolute percentage error <90%).ConclusionsA multi-compartmental brain pharmacokinetic model was developed and its structure could adequately describe data across nine different drugs. The model could be successfully translated to predict human brain concentrations.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-016-2065-3) contains supplementary material, which is available to authorized users.

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“…First, a combined drug dispersion parameter was estimated to capture the CSF and ECF flow and turbulence flow of the drug molecules (38,39). …”

Section: Methodsmentioning

confidence: 99%

A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations

et al. 2016

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“…For instance, cyclic deformation of the human brain induced by cardiovascular and respiratory action induces ventricular cerebrospinal fluid (CSF) motion with close to zero net flow that leads to substantial dispersion5. Similarly, dispersion occurs in the spinal canal through oscillatory CSF motion6.…”

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confidence: 99%

Glymphatic solute transport does not require bulk flow

Asgari

Zélicourt

Kurtcuoglu

2016

Sci Rep

239

304

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Observations of fast transport of fluorescent tracers in mouse brains have led to the hypothesis of bulk water flow directed from arterial to venous paravascular spaces (PVS) through the cortical interstitium. At the same time, there is evidence for interstitial solute transport by diffusion rather than by directed bulk fluid motion. It has been shown that the two views may be consolidated by intracellular water flow through astrocyte networks combined with mainly diffusive extracellular transport of solutes. This requires the presence of a driving force that has not been determined to date, but for which arterial pulsation has been suggested as the origin. Here we show that arterial pulsation caused by pulse wave propagation is an unlikely origin of this hypothetical driving force. However, we further show that such pulsation may still lead to fast para-arterial solute transport through dispersion, that is, through the combined effect of local mixing and diffusion in the para-arterial space.

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“…For example, the blood brain barrier (BBB), which is formed by a continuous layer of endothelial cells joined together by tight junctions (zonulae occludens) surrounding blood vessels [19,20], severely restricts access of large therapeutic molecules to the brain and spinal cord tissue. Previously, NP systems have been utilized to by-pass the BBB for treatment of CNS diseases like gliomas [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Quantum Dot Conjugated Magnetic Nanoparticles for Targeted Drug Delivery and Imaging

Venugopal¹,

Pernal²,

Fusinatto³

et al. 2016

Nano BioMed ENG

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Nanotechnology is being increasingly applied for developing drug delivery options for specific treatments. Magnetic nanoparticles have drawn attention as drug delivery vehicles due to their stability, biocompatibility and ability to be non-invasively guided to desired target areas using magnetic fields. In this paper, we describe a new delivery vehicle for magnetic drug targeting. In magnetic drug targeting, drug functionalized magnetic nanoparticles are guided and localized at specific sites using external magnetic fields. Magnetic nanoparticles act as contrast agents for magnetic resonance imaging. However, it cannot be visualized via this technique during drug delivery. This is between magnetic fields used for imaging and delivery can interference with each other. Our laboratory has synthesized a magnetic drug targeting vehicle conjugated with quantum dots that can be imaged during the drug delivery process with in vivo imaging techniques such as fluorescence molecular tomography. These nanocomposites can be used as drug delivery vehicles for the central nervous system, where drug targeting is especially difficult and minimizing side effects is critical.

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The Effect of Pulsatile Flow on Intrathecal Drug Delivery in the Spinal Canal

Cited by 67 publications

References 44 publications

A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations

A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations

Glymphatic solute transport does not require bulk flow

Quantum Dot Conjugated Magnetic Nanoparticles for Targeted Drug Delivery and Imaging

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