title: Differentiating the Effect of an Opioid Agonist on Cardiac Repolarization From µ-Receptor-mediated, Indirect Effects on the QT Interval: A Randomized, 3-way Crossover Study in Healthy Subjects.
abstract: OBJECTIVE
  A thorough QT study was conducted in healthy subjects to evaluate the effect of buprenorphine hydrochloride administered through a buccal soluble film under coverage of naltrexone to block confounding, secondary QT effects.
  
  
  METHODS
  Healthy subjects were enrolled in a randomized, partially blinded, 4-way crossover designed study. Subjects received buprenorphine 3 mg with naltrexone, naltrexone alone (with placebo films), placebo (placebo films and placebo naltrexone), and open-label moxifloxacin 400 mg with placebo naltrexone in separate in-house treatment periods. Naltrexone treatment (50 mg) was initiated 12 hours before buprenorphine and was given every 12 hours for a total of 4 doses. ECG data were extracted from a continuous recording predose and serially after dosing on the treatment day. ECG intervals were measured at a central ECG laboratory by using the high-precision QT technique. The QT interval was corrected for heart rate with Fridericia's formula (QTcF), and change-from-predose baseline QTcF (∆QTcF) was analyzed by using a mixed effect model.
  
  
  RESULTS
  Fifty-eight subjects (35 males) with a mean age of 32 were enrolled into the study. Treatment with buprenorphine 3 mg resulted in a small QT effect with the largest mean naltrexone-corrected ∆QTcF reaching 5.8 msec at 8 hours' postdosing (upper bound of the 90% CI below 10 msec). Exposure response analysis with a linear model demonstrated a significant linear relationship between plasma levels and naltrexone-corrected ∆QTcF, with an estimated mean slope of 0.65 msec per nanogram/milliliter (90% CI, 0.22 to 1.08). Using the exposure response model, an effect on ∆QTcF of 4.5 msec (2.80 to 6.12) can be predicted at the observed geometric peak plasma level after administration of the 3-mg buprenorphine dose in this study (3.6 ng/mL [3.33 to 3.98]). Naltrexone alone did not have a relevant effect on the QTcF interval.
  
  
  CONCLUSIONS
  The present study showed that buprenorphine plasma levels up to 5 ng/mL had no effect on the QTc above the level of clinical concern.
authors.affiliation: Karolinska Institute, Department of Clinical Sciences, Danderyd's Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden; iCardiac Technologies, Rochester, New York. Electronic address: borje.darpo@telia.com.
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.affiliation: iCardiac Technologies, Rochester, New York.
authors.forename: Meijian
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Endo Pharmaceuticals Inc, Malvern, Pennsylvania.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Bai
authors.affiliation: Statistik Georg Ferber GmbH, Riehen, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Ferber
authors.affiliation: Endo Pharmaceuticals Inc, Malvern, Pennsylvania.
authors.forename: Qinfang
authors.initials: Q
authors.lastname: Xiang
authors.affiliation: BioDelivery Sciences International, Raleigh, North Carolina.
authors.forename: Andrew
authors.initials: A
authors.lastname: Finn
mesh_terms: D000328:Adult; D002047:Buprenorphine / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D000077266:Moxifloxacin; D009271:Naltrexone / Q000494:pharmacology*
chemical_list: D024841:Fluoroquinolones; D002047:Buprenorphine; D009271:Naltrexone; D000077266:Moxifloxacin
keywords: QT prolongation; buprenorphine; naltrexone; opioids; thorough QT study; µ-receptor blockade