Clinical therapeutics · 2013
Effects of injectable HPβCD-diclofenac on the human delayed rectifier potassium channel current in vitro and on proarrhythmic QTc in vivo.
Сравнительное исследованиеСтатьяРандомизированное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Carr Daniel B, McDonnell Moorehead Tara, Bouchard Annie, Sprenger Craig R, Hamilton Douglas A, Lang Eric, Madden Donna, Lacouture Peter G, Wright Curtis
Аннотация
BACKGROUND: Novel formulations and administration routes of established drugs may result in higher maximum concentrations or total exposures and potentially cause previously unrecognized adverse events.
OBJECTIVE: This study evaluated the proarrhythmic potential of hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac, a novel injectable diclofenac formulation solubilized with hydroxypropyl-β-cyclodextrin (HPβCD), on ventricular electrical conduction in preclinical and clinical models.
METHODS: We assessed the effects of diclofenac, HPβCD, and HPβCD-diclofenac on the human delayed rectifier potassium channel (IKr) using human embryonic kidney (HEK) 293 cells transfected with a human ether-à-go-go-related gene (hERG) using whole-cell patch-clamp. In a single-dose, active- and placebo-controlled, 4-period crossover, thorough QT in vivo study, 70 healthy volunteers (mean age, 23.3 years; range, 18-49 years; 55.75% male) received HPβCD-diclofenac at 37.5- and 75-mg doses, inactive vehicle (placebo), and an active control (moxifloxacin).
RESULTS: In vitro, diclofenac produced no statistically significant effect on IKr. Significant, non-dose-dependent effects were observed in the presence of HPβCD or HPβCD-diclofenac of similar magnitude across the 300-fold dose range of concentrations tested, suggesting an artifact due to the detergent effect of HPβCD in this in vitro model. In vivo, neither HPβCD-diclofenac dose resulted in QTc prolongation ≥2 ms (≥5 ms is the threshold of clinical concern). No correlation was evident between changes in QTc and plasma concentrations of diclofenac or HPβCD. Confirming study sensitivity, moxifloxacin produced a mean QTc prolongation >10 ms.
CONCLUSIONS: The findings from the present study suggest that HPβCD-diclofenac does not have a dose-dependent effect in the in vitro hERG assay system and does not produce proarrhythmic QTc prolongation in vivo. ClinicalTrials.gov identifier: NCT01812538.
OBJECTIVE: This study evaluated the proarrhythmic potential of hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac, a novel injectable diclofenac formulation solubilized with hydroxypropyl-β-cyclodextrin (HPβCD), on ventricular electrical conduction in preclinical and clinical models.
METHODS: We assessed the effects of diclofenac, HPβCD, and HPβCD-diclofenac on the human delayed rectifier potassium channel (IKr) using human embryonic kidney (HEK) 293 cells transfected with a human ether-à-go-go-related gene (hERG) using whole-cell patch-clamp. In a single-dose, active- and placebo-controlled, 4-period crossover, thorough QT in vivo study, 70 healthy volunteers (mean age, 23.3 years; range, 18-49 years; 55.75% male) received HPβCD-diclofenac at 37.5- and 75-mg doses, inactive vehicle (placebo), and an active control (moxifloxacin).
RESULTS: In vitro, diclofenac produced no statistically significant effect on IKr. Significant, non-dose-dependent effects were observed in the presence of HPβCD or HPβCD-diclofenac of similar magnitude across the 300-fold dose range of concentrations tested, suggesting an artifact due to the detergent effect of HPβCD in this in vitro model. In vivo, neither HPβCD-diclofenac dose resulted in QTc prolongation ≥2 ms (≥5 ms is the threshold of clinical concern). No correlation was evident between changes in QTc and plasma concentrations of diclofenac or HPβCD. Confirming study sensitivity, moxifloxacin produced a mean QTc prolongation >10 ms.
CONCLUSIONS: The findings from the present study suggest that HPβCD-diclofenac does not have a dose-dependent effect in the in vitro hERG assay system and does not produce proarrhythmic QTc prolongation in vivo. ClinicalTrials.gov identifier: NCT01812538.
Предметные рубрики MeSH
2-Hydroxypropyl-beta-cyclodextrinAdolescentAdultAnti-Inflammatory Agents, Non-SteroidalArrhythmias, CardiacAza CompoundsCross-Over StudiesDiclofenacDose-Response Relationship, DrugERG1 Potassium ChannelEther-A-Go-Go Potassium ChannelsFemaleFluoroquinolonesHEK293 CellsHumansLong QT SyndromeMaleMiddle AgedMoxifloxacinPatch-Clamp TechniquesPotassium Channels, Inwardly RectifyingQuinolinesYoung Adultbeta-Cyclodextrins