First Clinical Experience With TRV130: Pharmacokinetics and Pharmacodynamics in Healthy Volunteers

@article{Soergel2014FirstCE,
  title={First Clinical Experience With TRV130: Pharmacokinetics and Pharmacodynamics in Healthy Volunteers},
  author={David G. Soergel and Ruth Ann Subach and Brian M. Sadler and John Connell and Alan S Marion and Conrad L. Cowan and Jonathan D. Violin and Michael W. Lark},
  journal={The Journal of Clinical Pharmacology},
  year={2014},
  volume={54}
}
TRV130 is a G protein‐biased ligand at the µ‐opioid receptor. In preclinical studies it was potently analgesic while causing less respiratory depression and gastrointestinal dysfunction than morphine, suggesting unique benefits in acute pain management. A first‐in‐human study was conducted with ascending doses of TRV130 to explore its tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers. TRV130 was well‐tolerated over the dose range 0.15 to 7 mg administered intravenously… 
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Initial dose reduction should be considered in severe hepatic impairment, and patients may require fewer doses of oliceridine due to the longer half‐life observed in these patients.
A randomized, phase 2 study investigating TRV130, a biased ligand of the &mgr;-opioid receptor, for the intravenous treatment of acute pain
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It is demonstrated that TRV130 rapidly produces profound analgesia in moderate-to-severe acute pain, suggesting that G-protein-biased &mgr;-opioid receptor activation is a promising target for development of novel analgesics.
Oliceridine (TRV130), a Novel G Protein–Biased Ligand at the μ‐Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. I: Development of a Pharmacokinetic/Pharmacodynamic Model
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A population pharmacokinetic/pharmacodynamic model linking the pharmacokinetics of oliceridine to its effect on pain, as measured by the Numeric Pain Rating Scale score is developed and showed that the model robustly reproduced the original data.
Oliceridine, a Novel G Protein–Biased Ligand at the μ‐Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. II: Simulation of Potential Phase 3 Study Designs Using a Pharmacokinetic/Pharmacodynamic Model
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Simulation results suggest that oliceridine doses of 1‐3 mg prn should be effective in reducing NPRS scores relative to placebo, and it is revealed that a 1‐mg “supplemental dose” given 0.25 hour after the loading dose would decreaseNPRS scores further in almost one‐third of patients.
Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers
How Oliceridine (TRV-130) Binds and Stabilizes a μ-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways.
TLDR
Simulation of ligand-receptor interactions for TRV-130, a G protein-biased MOR small-molecule agonist that has been shown to exert analgesia with less respiratory depression and constipation than morphine and that is currently being evaluated in human clinical trials for acute pain management, provides insights into the energetically preferred binding pathway of this ligand and its stable pose at the orthosteric binding site of MOR.
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TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea, demonstrating early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.
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The discovery and synthesis of TRV 130, its main action as a novel analgesic having less adverse events, its up-to-date status in clinical trials, and additional concerns about TRV130 as demonstrated in the literature are reviewed.
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Oliceridine will be an important addition to the clinical armamentarium for use for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate.
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A review of the preclinical and clinical data of intravenous oliceridine, a selective agonist, which has the potential to offer a wider therapeutic window than conventional opioids, is provided.
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