No effect on QT intervals of mipomersen, a 2′- O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects.
Purpose: The aim of this study to evaluate the effect of mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects. Methods: In the initial phase I study, 29 healthy subjects received either single or multiple (for 4 weeks) a...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 72; no. 3; pp. 267 - 276 |
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| Autores principales: | , , , , , , , , |
| Formato: | clinical trial equations & formulas research tables/charts Journal Article |
| Publicado: |
Springer Nature
Mar2016
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| 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=112926733&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 112926733 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Mar2016 vid: 72 iid: 3 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 112926733 112926733 112926733 10.1007/s00228-015-1992-y 112926733 ppf: 267 ppct: 9 formats: fmt: @attributes: type: P tig: atl: No effect on QT intervals of mipomersen, a 2′- O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects. aug: au: Yu, Rosie Gunawan, Rudy Li, Zhaoyang Mittleman, Robert Mahmood, Asif Grundy, John Singleton, Walter Geary, Richard Wang, Yanfeng affil: Isis Pharmaceuticals, Inc., 2855 Gazelle Court Carlsbad 92010 USA sug: subj: Antilipemic Agents Administration and Dosage Apolipoproteins Antagonists and Inhibitors Heart Drug Effects Clinical Trials Placebos Crossover Design Electrocardiography Linear Regression Human Antilipemic Agents Pharmacokinetics Antilipemic Agents Pharmacodynamics ab: Purpose: The aim of this study to evaluate the effect of mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects. Methods: In the initial phase I study, 29 healthy subjects received either single or multiple (for 4 weeks) ascending doses of mipomersen (50-400 mg) administered subcutaneously (SC) or via a 2-h intravenous (IV) infusion, and 7 subjects received placebo. In the confirmative tQT study, 58 healthy subjects received placebo, 400 mg IV moxifloxacin, 200 mg SC, or 200 mg IV of mipomersen in a double-blind, 4-way crossover design with a minimum 5-day washout between treatments. ECG measurements were performed at baseline and selected time points (including T). The correlation between QTcF intervals corrected for baseline and time-matched placebo when available with PK plasma exposure was evaluated by linear regression analysis. Results: In the phase I study, no positive correlation between the PK exposure and ∆QTcF or ∆∆QTcF was observed within the wide dose or exposure range tested. Similar results were observed in the tQT study, where the predicted ΔΔQTcF and its upper bound of the 90 % CI at C of therapeutic and supratherapeutic dose were approximately −1.7 and 2.9 ms, respectively. Conclusions: Mipomersen showed no effect on QT intervals in both the phase I dose escalation study and the tQT study. These results support the proposal that QT assessment can be made in a phase I dose escalation study, and no tQT study may be necessary if the phase I dose escalation study showed a negative QT effect. pubtype: Academic Journal doctype: clinical trial equations & formulas research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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