title: Development and validation of sensitive LC-MS/MS assays for quantification of HP-β-CD in human plasma and CSF.
abstract: 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used excipient for drug formulation, has emerged as an investigational new drug for the treatment of Niemann-Pick type C1 (NPC1) disease, a neurodegenerative cholesterol storage disorder. Development of a sensitive quantitative LC-MS/MS assay to monitor the pharmacokinetics (PKs) of HP-β-CD required for clinical trials has been challenging owing to the dispersity of the HP-β-CD. To support a phase 1 clinical trial for ICV delivery of HP-β-CD in NPC1 patients, novel methods for quantification of HP-β-CD in human plasma and cerebrospinal fluid (CSF) using LC-MS/MS were developed and validated: a 2D-LC-in-source fragmentation-MS/MS (2D-LC-IF-MS/MS) assay and a reversed phase ultra performance LC-MS/MS (RP-UPLC-MS/MS) assay. In both assays, protein precipitation and "dilute and shoot" procedures were used to process plasma and CSF, respectively. The assays were fully validated and in close agreement, and allowed determination of PK parameters for HP-β-CD. The LC-MS/MS methods are ∼100-fold more sensitive than the current HPLC assay, and were successfully employed to analyze HP-β-CD in human plasma and CSF samples to support the phase 1 clinical trial of HP-β-CD in NPC1 patients.
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO.
authors.forename: Rohini
authors.initials: R
authors.lastname: Sidhu
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO.
authors.forename: Hideji
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Janssen Research and Development, Springhouse, PA.
authors.forename: Marc
authors.initials: M
authors.lastname: De Meulder
authors.affiliation: Janssen Research and Development, Springhouse, PA.
authors.forename: Ronald
authors.initials: R
authors.lastname: de Vries
authors.affiliation: Beerse, Belgium, Janssen Research and Development, Springhouse, PA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Beerse, Belgium, Janssen Research and Development, Springhouse, PA.
authors.forename: Mark
authors.initials: M
authors.lastname: Kao
authors.affiliation: Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.affiliation: Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Yanjanin
authors.affiliation: Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Nuria
authors.initials: N
authors.lastname: Carillo-Carasco
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ottinger
authors.affiliation: Nursing Department, National Institutes of Health, Bethesda, MD.
authors.forename: Myra
authors.initials: M
authors.lastname: Woolery
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO.
authors.forename: Xuntian
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin / Q000097:blood* / Q000134:cerebrospinal fluid*; D002853:Chromatography, Liquid / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*
chemical_list: D000073738:2-Hydroxypropyl-beta-cyclodextrin
keywords: 2-hydroxypropyl-β-cyclodextrin; Niemann-Pick C; cerebrospinal fluid; in-source fragmentation; liquid chromatography-tandem mass spectrometry; two-dimensional liquid chromatography; ultra performance liquid chromatography