Investigation of the Brain Biodistribution of the Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitor [18F]GSK2647544 in Healthy Male Subjects.
Purpose: GSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), which was in development as a potential treatment for Alzheimer's disease (AD). In order to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhi...
| Publicado en: | Molecular Imaging & Biology Vol. 19; no. 1; pp. 153 - 162 |
|---|---|
| Autores principales: | , , , , , , , , , , , , , , |
| Formato: | clinical trial research Journal Article |
| Publicado: |
Springer Nature
Feb2017
|
| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=120531195&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 120531195 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 15361632 KJU jtl: Molecular Imaging & Biology issn: 15361632 maglogo: N pubinfo: dt: Feb2017 vid: 19 iid: 1 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 120531195 120531195 NLM27402093 120531195 10.1007/s11307-016-0982-5 NLM27402093 120531195 ppf: 153 ppct: 9 formats: fmt: @attributes: type: P tig: atl: Investigation of the Brain Biodistribution of the Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitor [18F]GSK2647544 in Healthy Male Subjects. aug: au: Huiban, Mickael Coello, Christopher Wu, Kai Xu, Yanmei Lewis, Yvonne Brown, Andrew Buraglio, Mauro Guan, Chenbing Shabbir, Shaila Fong, Regan Passchier, Jan Rabiner, Eugenii Lockhart, Andrew Brown, Andrew P Rabiner, Eugenii A affil: Imanova Limited, Burlington Danes Building, Imperial College London, Hammersmith Hospital , Du Cane Road London W12 0NN UK sug: subj: Brain Metabolism Phenyl Ethers Pharmacodynamics Heterocyclic Compounds Pharmacodynamics Phenyl Ethers Pharmacokinetics Heterocyclic Compounds Pharmacokinetics Fluorine Radioisotopes Esterases Antagonists and Inhibitors Rats Esterases Metabolism Phenyl Ethers Adverse Effects Image Processing, Computer Assisted Middle Age Heterocyclic Compounds Blood Phenyl Ethers Blood Animal Studies Adult Human Male Mice Time Factors Heterocyclic Compounds Adverse Effects Clinical Trials Validation Studies Comparative Studies Evaluation Research Multicenter Studies Middle Aged: 45-64 years Adult: 19-44 years Male ab: Purpose: GSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), which was in development as a potential treatment for Alzheimer's disease (AD). In order to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhibitor, [18F]GSK2647544, was manufactured for use in a positron emission tomography (PET) biodistribution study.Procedures: [18F]GSK2647544 was produced using a novel, copper iodide (Cu(I)) mediated, [18F]trifluoromethylation methodology. Healthy male subjects (n = 4, age range 34-42) received an oral dose of unlabelled GSK2647544 (100 mg) and after 2 h an intravenous (iv) injection of [18F]GSK2647544 (average injected activity and mass were 106 ± 47 MBq and 179 ± 55 μg, respectively) followed by dynamic PET scans for 120 min. Defined regions of interest (ROI) throughout the brain were used to obtain regional time-activity curves (TACs) and compartmental modelling analysis used to estimate the primary outcome measure, whole brain volume of distribution (VT). Secondary PK and safety endpoints were also recorded.Results: PET dynamic data were successfully obtained from all four subjects and there were no clinically significant variations of the safety endpoints. Inspection of the TACs indicated a relatively homogenous uptake of [18F]GSK2647544 across all the ROIs examined. The mean whole brain VT was 0.56 (95 % CI, 0.41-0.72). Secondary PK parameters, Cmax (geometric mean) and Tmax (median), were 354 ng/ml and 1.4 h, respectively. Metabolism of GSK2647544 was relatively consistent across subjects, with 20-40 % of the parent compound [18F]GSK2647544 present after 120 min.Conclusions: The study provides evidence that GSK2647544 is able to cross the blood brain barrier in healthy male subjects leading to a measurable brain exposure. The administered doses of GSK2647544 were well tolerated. Exploratory modelling suggested that a twice-daily dose of 102 mg, at steady state, would provide ~80 % trough inhibition of brain Lp-PLA2 activity.Trial Registration: Clintrials.gov: NCT01924858. pubtype: Academic Journal doctype: clinical trial research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
|---|