title: Effects of injectable HPβCD-diclofenac on the human delayed rectifier potassium channel current in vitro and on proarrhythmic QTc in vivo.
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.
authors.affiliation: Javelin Pharmaceuticals, Inc (now Hospira, Inc), Cambridge, MA, USA. daniel.carr@tufts.edu
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Carr
authors.forename: Tara
authors.initials: T
authors.lastname: McDonnell Moorehead
authors.forename: Annie
authors.initials: A
authors.lastname: Bouchard
authors.forename: Craig R
authors.initials: CR
authors.lastname: Sprenger
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Hamilton
authors.forename: Eric
authors.initials: E
authors.lastname: Lang
authors.forename: Donna
authors.initials: D
authors.lastname: Madden
authors.forename: Peter G
authors.initials: PG
authors.lastname: Lacouture
authors.forename: Curtis
authors.initials: C
authors.lastname: Wright
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001372:Aza Compounds / Q000009:adverse effects; D018592:Cross-Over Studies; D004008:Diclofenac / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005260:Female; D024841:Fluoroquinolones; D057809:HEK293 Cells; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects*; D011804:Quinolines / Q000009:adverse effects; D055815:Young Adult; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001372:Aza Compounds; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; C000606913:KCNH2 protein, human; D024661:Potassium Channels, Inwardly Rectifying; D011804:Quinolines; D047392:beta-Cyclodextrins; D004008:Diclofenac; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000077266:Moxifloxacin