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
| Autor: | Zhaoyang Li, Walter Singleton, Rudy Gunawan, Robert S. Mittleman, Asif Mahmood, Rosie Z. Yu, John S. Grundy, Richard S. Geary, Yanfeng Wang |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Apolipoprotein B Mipomersen Oligonucleotides Placebo-controlled study Cmax 030204 cardiovascular system & hematology Pharmacology Placebo 030226 pharmacology & pharmacy QT interval Oligodeoxyribonucleotides Antisense Electrocardiography Young Adult 03 medical and health sciences 0302 clinical medicine Double-Blind Method Moxifloxacin Humans Medicine Pharmacology (medical) RNA Messenger Cross-Over Studies biology business.industry General Medicine Middle Aged Crossover study Healthy Volunteers Apolipoprotein B-100 biology.protein Female business medicine.drug |
| Zdroj: | European Journal of Clinical Pharmacology. 72:267-275 |
| ISSN: | 1432-1041 0031-6970 |
| Popis: | 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. 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 Tmax). The correlation between QTcF intervals corrected for baseline and time-matched placebo when available with PK plasma exposure was evaluated by linear regression analysis. 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 Cmax of therapeutic and supratherapeutic dose were approximately −1.7 and 2.9 ms, respectively. 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. |
| Databáze: | OpenAIRE |
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