Elsevier

Heart Rhythm

Volume 18, Issue 12, December 2021, Pages 2177-2186
Heart Rhythm

Experimental
Intracellular uptake of agents that block the hERG channel can confound the assessment of QT interval prolongation and arrhythmic risk

https://doi.org/10.1016/j.hrthm.2021.08.028Get rights and content

Background

Oliceridine is a biased ligand at the μ-opioid receptor recently approved for the treatment of acute pain. In a thorough QT study, corrected QT (QTc) prolongation displayed peaks at 2.5 and 60 minutes after a supratherapeutic dose. The mean plasma concentration peaked at 5 minutes, declining rapidly thereafter.

Objective

The purpose of this study was to examine the basis for the delayed effect of oliceridine to prolong the QTc interval.

Methods

Repolarization parameters and tissue accumulation of oliceridine were evaluated in rabbit left ventricular wedge preparations over a period of 5 hours. The effects of oliceridine on ion channel currents were evaluated in human embryonic kidney and Chinese hamster ovary cells. Quinidine was used as a control.

Results

Oliceridine and quinidine produced a progressive prolongation of the QTc interval and action potential duration over a period of 5 hours, paralleling slow progressive tissue uptake of the drugs. Oliceridine caused modest prolongation of these parameters, whereas quinidine produced a prominent prolongation of action potential duration and QTc interval as well as development of early afterdepolarization (after 2 hours), resulting in a high torsades de pointes score. The 50% inhibitory concentration values for the oliceridine inhibition of the rapidly activating delayed rectifier current (human ether a-go-go current) and late sodium channel current were 2.2 and 3.45 μM when assessed after traditional acute exposure but much lower after 3 hours of drug exposure.

Conclusion

Our findings suggest that a gradual increase of intracellular access of drugs to the hERG channels as a result of their intracellular uptake and accumulation can significantly delay effects on repolarization, thus confounding the assessment of QT interval prolongation and arrhythmic risk when studied acutely. The multi-ion channel effects of oliceridine, late sodium channel current inhibition in particular, point to a low risk of devloping torsades de pointes.

Introduction

Oliceridine is a biased ligand at the μ-opioid receptor recently approved for the treatment of acute pain in adult patients for whom an intravenous opioid is warranted and for whom other treatments have proved inadequate. In a thorough QT (TQT) study designed to assess its QT liability, oliceridine (intravenous injection for 5 minutes) caused 2 peaks in placebo- and baseline-corrected QT (QTc) prolongation, the first at 2.5 minutes and the second at 60 minutes after a supratherapeutic dose of 6 mg (Figure 1). The plasma concentration of oliceridine reached a peak within minutes (6 mg; the time it takes to reach Cmax = 5 minutes; the maximum concentration recorded [Cmax] = 283.9 ng/mL) and declined rapidly thereafter (Figure 1). The principal aim of the present study was to advance our understanding of the cellular mechanisms underlying the actions of oliceridine. The study was specifically designed to elucidate (1) the mechanism underlying the effect of oliceridine to transiently prolong the QT interval as well as (2) the mechanism(s) underlying the approximately 1 hour delay in the attainment of peak QT interval prolongation observed after a 6 mg (supratherapeutic) bolus of oliceridine in the TQT study (Figure 1). Our study tests the hypothesis that the delay in the attainment of peak QT interval prolongation is due to progressively increasing intracellular access of the drug to hERG channels secondary to its intracellular uptake and accumulation. The protocols used are designed to compare the time course of the effect of oliceridine to prolong the endocardial action potential duration (APD), QT interval, and QRS interval with the time course of the intracellular accumulation of oliceridine in rabbit left ventricular wedge preparations. Quinidine was selected as a positive control because it has similarly been reported to cause a delayed effect on ventricular repolarization in both clinical and experimental studies.1, 2, 3

Section snippets

Rabbit isolated coronary-perfused left ventricular preparations

The investigation was performed according to the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication N85-23, revised 1985). The study was approved by the Institutional Animal Care and Use Committee of the Lankenau Institute for Medical Research. Rabbits were initially given xylazine at a dose of 4–8 mg/kg intramuscularly. Once sedated, rabbits were anticoagulated with heparin (human pharmaceutical grade, 1000 U/kg intravenously) and

Ion channel current data

Figure 2 shows the effect of oliceridine to inhibit IKr (hERG channels) stably expressed in human embryonic kidney cells. Analysis of the data yields a 50% inhibitory concentration (IC50) of 2.2 mM. Figure 3 shows the inhibitory effect of oliceridine on late INa (IC50 3.45 mM). Table 1 summarizes the IC50 values for oliceridine block of hERG, CaV1.2, and NaV1.5 (tonic and phasic) and late INa channels. The table includes the effects of oliceridine’s major metabolites. Based on the relatively

Discussion

Opioid analgesics such as morphine, fentanyl, and hydromorphone are mainstays of therapy in the management of pain. Their use is hampered by well-known adverse effects, including respiratory depression, nausea, vomiting, prolonged ileus, and sedation. The adverse effects of opioids impact patient recovery in different ways: the threat of respiratory depression may lead to underdosing of opioids, gastrointestinal adverse effects may delay oral intake and may thereby prolong the patient’s stay in

Conclusion

Our experimenal findings indicate that the oliceridine-induced concentration-QT effect hysterisis observed in the clinical thorough QTc study is due to gradual uptake and accumulation of oliceridine in cardiac tissues and cells. Our results point to a low probability of oliceridine to cause TdP compared with quinidine because of the drug’s multi-ion channel effects, particulary its ability to block late INa. Our data also indicate that intracellular uptake and accumulation of agents that block

References (17)

There are more references available in the full text version of this article.

Cited by (2)

Funding sources: This study was supported by the National Institutes of Health (grant nos. HL47678, HL138103, and HL152201), Trevena, W.W. Smith Charitable Trust, and Wistar and Martha Morris Fund.

Disclosures: Drs Antzelevitch, Burashnikov, and Barajas-Martinez have received grant funds from Trevena. Drs Kowey and Kleiman are consultants to Trevena. Dr Demitrack, Fossler, and Kramer are employees of Trevena. Dr Cox reports no conflicts of interest.

View full text