Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders
Abstract Background Quantitative measurements of cerebrospinal fluid to blood clearance has previously not been established for neurological diseases. Possibly, variability in cerebrospinal fluid clearance may affect the underlying disease process and may possibly be a source of under- or over-dosag...
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| Format: | Article |
| Language: | English |
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BMC
2022-07-01
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| Series: | Fluids and Barriers of the CNS |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12987-022-00352-w |
| _version_ | 1828336328128856064 |
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| author | Markus Herberg Hovd Espen Mariussen Hilde Uggerud Aslan Lashkarivand Hege Christensen Geir Ringstad Per Kristian Eide |
| author_facet | Markus Herberg Hovd Espen Mariussen Hilde Uggerud Aslan Lashkarivand Hege Christensen Geir Ringstad Per Kristian Eide |
| author_sort | Markus Herberg Hovd |
| collection | DOAJ |
| description | Abstract Background Quantitative measurements of cerebrospinal fluid to blood clearance has previously not been established for neurological diseases. Possibly, variability in cerebrospinal fluid clearance may affect the underlying disease process and may possibly be a source of under- or over-dosage of intrathecally administered drugs. The aim of this study was to characterize the cerebrospinal fluid to blood clearance of the intrathecally administered magnetic resonance imaging contrast agent gadobutrol (Gadovist, Bayer Pharma AG, GE). For this, we established a population pharmacokinetic model, hypothesizing that cerebrospinal fluid to blood clearance differs between cerebrospinal fluid diseases. Methods Gadobutrol served as a surrogate tracer for extra-vascular pathways taken by several brain metabolites and drugs in cerebrospinal fluid. We estimated cerebrospinal fluid to blood clearance in patients with different cerebrospinal fluid disorders, i.e. symptomatic pineal and arachnoid cysts, as well as tentative spontaneous intracranial hypotension due to cerebrospinal fluid leakage, idiopathic intracranial hypertension, or different types of hydrocephalus (idiopathic normal pressure hydrocephalus, communicating- and non-communicating hydrocephalus). Individuals with no verified cerebrospinal fluid disturbance at clinical work-up were denoted references. Results Population pharmacokinetic modelling based on 1,140 blood samples from 161 individuals revealed marked inter-individual variability in pharmacokinetic profiles, including differences in absorption half-life (time to 50% of tracer absorbed from cerebrospinal fluid to blood), time to maximum concentration in blood and the maximum concentration in blood as well as the area under the plasma concentration time curve from zero to infinity. In addition, the different disease categories of cerebrospinal fluid diseases demonstrated different profiles. Conclusions The present observations of considerable variation in cerebrospinal fluid to blood clearance between individuals in general and across neurological diseases, may suggest that defining cerebrospinal fluid to blood clearance can become a useful diagnostic adjunct for work-up of cerebrospinal fluid disorders. We also suggest that it may become useful for assessing clearance capacity of endogenous brain metabolites from cerebrospinal fluid, as well as measuring individual cerebrospinal fluid to blood clearance of intrathecal drugs. |
| first_indexed | 2024-04-13T21:59:30Z |
| format | Article |
| id | doaj.art-b92176d348f54b60bf6d79f4bb783667 |
| institution | Directory Open Access Journal |
| issn | 2045-8118 |
| language | English |
| last_indexed | 2024-04-13T21:59:30Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Fluids and Barriers of the CNS |
| spelling | doaj.art-b92176d348f54b60bf6d79f4bb7836672022-12-22T02:28:08ZengBMCFluids and Barriers of the CNS2045-81182022-07-0119111410.1186/s12987-022-00352-wPopulation pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disordersMarkus Herberg Hovd0Espen Mariussen1Hilde Uggerud2Aslan Lashkarivand3Hege Christensen4Geir Ringstad5Per Kristian Eide6Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of OsloNorwegian Institute for Air ResearchNorwegian Institute for Air ResearchDepartment of Neurosurgery, Oslo University Hospital—RikshospitaletSection for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of OsloDivision of Radiology and Nuclear Medicine, Department of Radiology, Oslo University Hospital—RikshospitaletDepartment of Neurosurgery, Oslo University Hospital—RikshospitaletAbstract Background Quantitative measurements of cerebrospinal fluid to blood clearance has previously not been established for neurological diseases. Possibly, variability in cerebrospinal fluid clearance may affect the underlying disease process and may possibly be a source of under- or over-dosage of intrathecally administered drugs. The aim of this study was to characterize the cerebrospinal fluid to blood clearance of the intrathecally administered magnetic resonance imaging contrast agent gadobutrol (Gadovist, Bayer Pharma AG, GE). For this, we established a population pharmacokinetic model, hypothesizing that cerebrospinal fluid to blood clearance differs between cerebrospinal fluid diseases. Methods Gadobutrol served as a surrogate tracer for extra-vascular pathways taken by several brain metabolites and drugs in cerebrospinal fluid. We estimated cerebrospinal fluid to blood clearance in patients with different cerebrospinal fluid disorders, i.e. symptomatic pineal and arachnoid cysts, as well as tentative spontaneous intracranial hypotension due to cerebrospinal fluid leakage, idiopathic intracranial hypertension, or different types of hydrocephalus (idiopathic normal pressure hydrocephalus, communicating- and non-communicating hydrocephalus). Individuals with no verified cerebrospinal fluid disturbance at clinical work-up were denoted references. Results Population pharmacokinetic modelling based on 1,140 blood samples from 161 individuals revealed marked inter-individual variability in pharmacokinetic profiles, including differences in absorption half-life (time to 50% of tracer absorbed from cerebrospinal fluid to blood), time to maximum concentration in blood and the maximum concentration in blood as well as the area under the plasma concentration time curve from zero to infinity. In addition, the different disease categories of cerebrospinal fluid diseases demonstrated different profiles. Conclusions The present observations of considerable variation in cerebrospinal fluid to blood clearance between individuals in general and across neurological diseases, may suggest that defining cerebrospinal fluid to blood clearance can become a useful diagnostic adjunct for work-up of cerebrospinal fluid disorders. We also suggest that it may become useful for assessing clearance capacity of endogenous brain metabolites from cerebrospinal fluid, as well as measuring individual cerebrospinal fluid to blood clearance of intrathecal drugs.https://doi.org/10.1186/s12987-022-00352-wCerebrospinal fluidClearanceGadobutrolBrain metabolitesIntrathecal administrationIntrathecal drugs |
| spellingShingle | Markus Herberg Hovd Espen Mariussen Hilde Uggerud Aslan Lashkarivand Hege Christensen Geir Ringstad Per Kristian Eide Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders Fluids and Barriers of the CNS Cerebrospinal fluid Clearance Gadobutrol Brain metabolites Intrathecal administration Intrathecal drugs |
| title | Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders |
| title_full | Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders |
| title_fullStr | Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders |
| title_full_unstemmed | Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders |
| title_short | Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders |
| title_sort | population pharmacokinetic modeling of csf to blood clearance prospective tracer study of 161 patients under work up for csf disorders |
| topic | Cerebrospinal fluid Clearance Gadobutrol Brain metabolites Intrathecal administration Intrathecal drugs |
| url | https://doi.org/10.1186/s12987-022-00352-w |
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