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