Effects of injectable HPβCD-diclofenac on the human delayed rectifier potassium channel current in vitro and on proarrhythmic QTc in vivo
Daniel B Carr, Tara McDonnell Moorehead, Annie Bouchard, Craig R Sprenger, Douglas A Hamilton, Eric Lang, Donna Madden, Peter G Lacouture, Curtis Wright 4th, Daniel B Carr, Tara McDonnell Moorehead, Annie Bouchard, Craig R Sprenger, Douglas A Hamilton, Eric Lang, Donna Madden, Peter G Lacouture, Curtis Wright 4th
Abstract
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.
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Source: PubMed