RESUMO
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-ß-cyclodextrin (HPßCD)-diclofenac, a novel injectable diclofenac formulation solubilized with hydroxypropyl-ß-cyclodextrin (HPßCD), on ventricular electrical conduction in preclinical and clinical models. METHODS: We assessed the effects of diclofenac, HPßCD, and HPßCD-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 HPßCD-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 HPßCD or HPßCD-diclofenac of similar magnitude across the 300-fold dose range of concentrations tested, suggesting an artifact due to the detergent effect of HPßCD in this in vitro model. In vivo, neither HPßCD-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 HPßCD. Confirming study sensitivity, moxifloxacin produced a mean QTc prolongation >10 ms. CONCLUSIONS: The findings from the present study suggest that HPßCD-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.
