title: Central nervous system disposition and metabolism of Fosdevirine (GSK2248761), a non-nucleoside reverse transcriptase inhibitor: an LC-MS and Matrix-assisted laser desorption/ionization imaging MS investigation into central nervous system toxicity.
abstract: The CNS disposition and metabolism of Fosdevirine (FDV), an HIV non-nucleoside reverse transcriptase inhibitor, was investigated in four patients who unexpectedly experienced seizures after at least 4 weeks of treatment in a Phase IIb, HIV-1 treatment experienced study. In addition, the CNS disposition and metabolism of FDV was examined in samples from rabbit, minipig, and monkey studies. LC-MS was used to characterize and estimate the concentrations of FDV and its metabolites in cerebral spinal fluid (seizure patients, rabbit, and monkey) and brain homogenate (rabbit, minipig, and monkey). The application of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) provided the spatial distribution of FDV and its metabolites in brain tissue (rabbit, minipig, and monkey). A cysteine conjugate metabolite resulting from an initial glutathione (GSH) Michael addition to the trans-phenyl acrylonitrile moiety of FDV was the predominant drug-related component in the samples from seizure patients, rabbits, and minipigs. This metabolite persisted in the CNS for an extended period of time after the last dose in both seizure patients and minipigs. Furthermore, the localization of this metabolite was found to be highly associated with the white matter in rabbit and minipig brain sections by MALDI IMS. In contrast, the predominant component in monkey CNS was FDV, which was shown to be highly associated with the gray matter. On the basis of these data, several hypothesizes are considered, which might provide insights into species differences in CNS toxicity/seizures observed after FDV dosing.
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. steve.x.castellino@gsk.com
authors.forename: Stephen
authors.initials: S
authors.lastname: Castellino
authors.forename: M Reid
authors.initials: MR
authors.lastname: Groseclose
authors.forename: James
authors.initials: J
authors.lastname: Sigafoos
authors.forename: David
authors.initials: D
authors.lastname: Wagner
authors.forename: Mark
authors.initials: M
authors.lastname: de Serres
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Polli
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Romach
authors.forename: James
authors.initials: J
authors.lastname: Myer
authors.forename: Brad
authors.initials: B
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D002853:Chromatography, Liquid / Q000379:methods; D005260:Female; D000882:Haplorhini; D006801:Humans; D007211:Indoles / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000633:toxicity; D008297:Male; D010721:Phosphinic Acids / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000633:toxicity; D011817:Rabbits; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000633:toxicity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods*; D013552:Swine; D013556:Swine, Miniature
chemical_list: C534138:IDX 899; D007211:Indoles; D010721:Phosphinic Acids; D018894:Reverse Transcriptase Inhibitors