Dataset Information

Exploring occupancy of the histamine H₃ receptor by pitolisant in humans using PET.

ABSTRACT:

Background and purpose

BF2.649 (pitolisant, Wakix®) is a novel histamine H₃ receptor inverse agonist/antagonist recently approved for the treatment of narcolepsy disorder. The objective of the study was to investigate in vivo occupancy of H₃ receptors by BF2.649 using PET brain imaging with the H₃ receptor antagonist radioligand [¹¹ C]GSK189254.

Experimental approach

Six healthy adult participants were scanned with [¹¹ C]GSK189254. Participants underwent a total of two PET scans on separate days, 3 h after oral administration of placebo or after pitolisant hydrochloride (40 mg). [¹¹ C]GSK189254 regional total distribution volumes were estimated in nine brain regions of interest with the two tissue-compartment model with arterial input function using a common V_ND across the regions. Brain receptor occupancies were calculated with the Lassen plot.

Key results

Pitolisant, at the dose administered, provided high (84 ± 7%; mean ± SD) occupancy of H₃ receptors. The drug was well-tolerated, and participants experienced few adverse events.

Conclusion and implications

The administration of pitolisant (40 mg) produces a high occupancy of H₃ receptors and may be a new tool for the treatment of a variety of CNS disorders that are associated with mechanisms involving H₃ receptors.

SUBMITTER: Rusjan P

PROVIDER: S-EPMC7348085 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Publications

Exploring occupancy of the histamine H<sub>3</sub> receptor by pitolisant in humans using PET.

Rusjan Pablo P Sabioni Pamela P Di Ciano Patricia P Mansouri Esmaeil E Boileau Isabelle I Laveillé Alexia A Capet Marc M Duvauchelle Thierry T Schwartz Jean-Charles JC Robert Philippe P Le Foll Bernard B

British journal of pharmacology 20200523 15

<h4>Background and purpose</h4>BF2.649 (pitolisant, Wakix®) is a novel histamine H<sub>3</sub> receptor inverse agonist/antagonist recently approved for the treatment of narcolepsy disorder. The objective of the study was to investigate in vivo occupancy of H<sub>3</sub> receptors by BF2.649 using PET brain imaging with the H<sub>3</sub> receptor antagonist radioligand [<sup>11</sup> C]GSK189254.<h4>Experimental approach</h4>Six healthy adult participants were scanned with [<sup>11</sup> C]GSK18 ...[more]

PMID: 32293706

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Project description:PurposeHere, 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.MethodsEleven 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.ResultsSV2A 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.ConclusionPlasma 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 registrationNCT05450822. Retrospectively registered 5 July 2022 https://clinicaltrials.gov/ct2/results? term=NCT05450822&Search=Search.

Dataset Information

Exploring occupancy of the histamine H₃ receptor by pitolisant in humans using PET.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Exploring occupancy of the histamine H<sub>3</sub> receptor by pitolisant in humans using PET.

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OmicsDI is part of the ELIXIR infrastructure

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Exploring occupancy of the histamine H3 receptor by pitolisant in humans using PET.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Exploring occupancy of the histamine H<sub>3</sub> receptor by pitolisant in humans using PET.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Exploring occupancy of the histamine H₃ receptor by pitolisant in humans using PET.