The BrainDrugs-epilepsy study: A prospective open-label cohort precision medicine study in epilepsy

Marstrand-Joergensen, Maja R.; Dam, Vibeke H.; Vinter, Kirsten; Ip, Cheng-Teng; Jensen, Kristian Reveles; Jørgensen, Martin Balslev; Hoei-Hansen, Christina E.; Ozenne, Brice; Fisher, Patrick M.; Knudsen, Gitte M.; Pinborg, Lars H.

doi:10.1016/j.nsa.2023.101136

Neuroscience Applied

2023

DOI: 10.1016/j.nsa.2023.101136

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The BrainDrugs-epilepsy study: A prospective open-label cohort precision medicine study in epilepsy

Maja R. Marstrand-Joergensen,

Vibeke H. Dam,

Kirsten Vinter

et al.

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Cited by 2 publications

References 138 publications

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Assessment of cerebral drug occupancy in humans using a single PET-scan: A [11C]UCB-J PET study

Marstrand-Joergensen,

Laurell,

Herrmann

et al. 2024

Eur J Nucl Med Mol Imaging

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Purpose Here, we evaluate a PET displacement model with a Single-step and Numerical solution in healthy individuals using the synaptic vesicle glycoprotein (SV2A) PET-tracer [11C]UCB-J and the anti-seizure medication levetiracetam (LEV). We aimed to (1) validate the displacement model by comparing the brain LEV-SV2A occupancy from a single PET scan with the occupancy derived from two PET scans and the Lassen plot and (2) determine the plasma LEV concentration-SV2A occupancy curve in healthy individuals. Methods Eleven healthy individuals (five females, mean age 35.5 [range: 25–47] years) underwent two 120-min [11C]UCB-J PET scans where an LEV dose (5–30 mg/kg) was administered intravenously halfway through the first PET scan to partially displace radioligand binding to SV2A. Five individuals were scanned twice on the same day; the remaining six were scanned once on two separate days, receiving two identical LEV doses. Arterial blood samples were acquired to determine the arterial input function and plasma LEV concentrations. Using the displacement model, the SV2A-LEV target engagement was calculated and compared with the Lassen plot method. The resulting data were fitted with a single-site binding model. Results SV2A occupancies and VND estimates derived from the displacement model were not significantly different from the Lassen plot (p = 0.55 and 0.13, respectively). The coefficient of variation was 14.6% vs. 17.3% for the Numerical and the Single-step solution in Bland-Altman comparisons with the Lassen plot. The average half maximal inhibitory concentration (IC50), as estimated from the area under the curve of the plasma LEV concentration, was 12.5 µg/mL (95% CI: 5–25) for the Single-Step solution, 11.8 µg/mL (95% CI: 4–25) for the Numerical solution, and 6.3 µg/mL (95% CI: 0.08-21) for the Lassen plot. Constraining Emax to 100% did not significantly improve model fits. Conclusion Plasma LEV concentration vs. SV2A occupancy can be determined in humans using a single PET scan displacement model. The average concentration of the three computed IC50 values ranges between 6.3 and 12.5 µg/mL. The next step is to use the displacement model to evaluate LEV occupancy and corresponding plasma concentrations in relation to treatment efficacy. Clinical trial registration NCT05450822. Retrospectively registered 5 July 2022 https://clinicaltrials.gov/ct2/results? term=NCT05450822&Search=Search.

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Assessment of cerebral drug occupancy in humans using a single PET-scan: A [11C]UCB-J PET study

Marstrand-Joergensen,

Laurell,

Herrmann

et al. 2024

Eur J Nucl Med Mol Imaging

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A Revolutionary Approach for Combating Efflux Transporter-mediated Resistant Epilepsy: Advanced Drug Delivery Systems

Tonk,

Singh,

Sharma

et al. 2025

CPD

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Epilepsy is a persistent neurological condition that affects 60 million individuals globally, with recurrent spontaneous seizures affecting 80% of patients. Antiepileptic drugs (AEDs) are the main course of therapy for approximately 65% of epileptic patients, and the remaining 35% develop resistance to medication, which leads to Drug-Resistant Epilepsy (DRE). DRE continues to be an important challenge in clinical epileptology. There are several theories that attempt to explain the neurological causes of pharmacoresistance in epilepsy. The theory that has been studied the most is the transporter hypothesis. Therefore, it is believed that upregulation of multidrug efflux transporters at the blood-brain barrier (BBB), such as P-glycoprotein (P-gp), which extrudes AEDs from their target location, is the major cause, leading to pharmacoresistance in epilepsy. The most effective strategies for managing this DRE are peripheral and central inhibition of P-gp and maintaining an effective concentration of the drug in the brain parenchyma. Presently, no medicinal product that inhibits P-gp is being used in clinical practice. In this review, several innovative and promising treatment methods, including gene therapy, intracranial injections, Pgp inhibitors, nanocarriers, and precision medicine, are discussed. The primary goal of this work is to review the P-gp transporter, its substrates, and the latest novel treatment methods for the management of DRE.

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The BrainDrugs-epilepsy study: A prospective open-label cohort precision medicine study in epilepsy

Cited by 2 publications

References 138 publications

Assessment of cerebral drug occupancy in humans using a single PET-scan: A [11C]UCB-J PET study

Assessment of cerebral drug occupancy in humans using a single PET-scan: A [11C]UCB-J PET study

A Revolutionary Approach for Combating Efflux Transporter-mediated Resistant Epilepsy: Advanced Drug Delivery Systems

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