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

• Published in: CLINICAL THERAPEUTICS Vol. 38; no. 2; pp. 315 - 326
• Main Authors: Darpo, Borje, Zhou, Meijian, Bai, Stephen A., Ferber, Georg, Xiang, Qinfang, Finn, Andrew
• Format: Journal Article Publication
• Language: English
• Published: United States Elsevier Inc 01.02.2016; Elsevier Limited
• Subjects: Adult; buprenorphine; Buprenorphine - pharmacology; Cardiac arrhythmia; Cross-Over Studies; Double-Blind Method; Drug dosages; Electrocardiography; Electrocardiography - drug effects; Female; Fluoroquinolones - pharmacology; Fridericia; Heart - drug effects; Heart Rate - drug effects; Humans; Internal Medicine; Laboratories; Long QT syndrome; Male; Medical Education; naltrexone; Naltrexone - pharmacology; opioids; Pain; Pharmaceuticals; Plasma; QT prolongation; Stock options; Substance abuse treatment; thorough QT study; µ-receptor blockade; United States > US; µ-receptor blockade; naltrexone; buprenorphine; QT prolongation; thorough QT study; opioids
• ISSN: 0149-2918; 1879-114X; 1879-114X
• DOI: 10.1016/j.clinthera.2015.12.004

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. 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. 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. 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.