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.
Highlights
2-Hydroxypropyl--cyclodextrin (HP--CD), a widely used excipient for drug formulation, has emerged as an investigational new drug for the treatment of NiemannPick type C1 (NPC1) disease, a neurodegenerative cholesterol storage disorder
NPC1 disease is characterized by an accumulation of Abbreviations: AUC, area under the concentration-time curve; AUMC, area under the first moment curve; Cmax, maximum drug concentration; CL, clearance; CSF, cerebrospinal fluid; CV, coefficient of variance; 2D-LC-IF-MS/MS, 2D-LC-in-source fragmentation-MS/MS; HILIC, hydrophilic interaction liquid chromatography; HP--CD, 2-hydroxypropyl--cyclodextrin; high QC (HQC), high quality control; ICV, intracerebroventricular; IS, internal standard; LLOQ, lower limit of quantification; low QC (LQC), low quality control; , the terminal rate constant; medium QC (MQC), medium quality control; MRM, multiple reaction monitoring; NIH, National Institutes of Health, NPC1, Niemann-Pick type C1; PK, pharmacokinetics; QC, quality control; RPLC, reversed phase liquid chromatography; reversed phase ultra performance liquid chromatography (RP-UPLC)-MS/MS, reversed phase-ultra performance LC-MS/MS; t1/2, terminal half-life; to reach Cmax (Tmax), time to reach the maximum dru1gTocownhcoemntrcaotirorens;pVodnsds,evnocluemsheoouflddibsteriabdudtiroensseadt .steady-state
Individual use investigational new drug applications for HP--CD have been allowed for eight pediatric patients in the US, and a phase 1 trial for delivery of HP--CD directly into the lateral ventricle of NPC1 patients was initiated in January 2013 at the National Institutes of Health (NIH) [8]
Summary
2-Hydroxypropyl--cyclodextrin (HP--CD), a widely used excipient for drug formulation, has emerged as an investigational new drug for the treatment of NiemannPick type C1 (NPC1) disease, a neurodegenerative cholesterol storage disorder. To support a phase 1 clinical trial for ICV delivery of HP--CD in NPC1 patients, novel methods for quantification of HP--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. NPC1 disease is characterized by an accumulation of Abbreviations: AUC, area under the concentration-time curve; AUMC, area under the first moment curve; Cmax, maximum drug concentration; CL, clearance; CSF, cerebrospinal fluid; CV, coefficient of variance; 2D-LC-IF-MS/MS, 2D-LC-in-source fragmentation-MS/MS; HILIC, hydrophilic interaction liquid chromatography; HP--CD, 2-hydroxypropyl--cyclodextrin; HQC, high quality control; ICV, intracerebroventricular; IS, internal standard; LLOQ, lower limit of quantification; LQC, low quality control; , the terminal rate constant; MQC, medium quality control; MRM, multiple reaction monitoring; NIH, National Institutes of Health, NPC1, Niemann-Pick type C1; PK, pharmacokinetics; QC, quality control; RPLC, reversed phase liquid chromatography; RP-UPLC-MS/MS, reversed phase-ultra performance LC-MS/MS; t1/2, terminal half-life; Tmax, time to reach the maximum dru1gTocownhcoemntrcaotirorens;pVodnsds,evnocluemsheoouflddibsteriabdudtiroensseadt .steady-state. To support the clinical trial, a reliable assay capable of quantifying HP--CD in human plasma and cerebrospinal fluid (CSF) was essential
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