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

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• 作者：Borje Darpo ; MD ; PhD¹ ; ² ; ^{borje.darpo@telia.com" class="auth_mail" title="E-mail the corresponding author} ; Meijian Zhou ; PhD² ; Stephen A. Bai ; PhD³ ; ^⁎ ; Georg Ferber ; PhD⁴ ; Qinfang Xiang ; PhD³ ; Andrew Finn ; PharmD⁵
• 关键词：µ ; -receptor blockade ; buprenorphine ; naltrexone ; opioids ; QT prolongation ; thorough QT study
• 刊名：Clinical Therapeutics
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：38
• 期：2
• 页码：315-326
• 全文大小：437 K

文摘

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.

Findings

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.

Implications

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.