A First-in-Human Clinical Study With TRV734, an Orally Bioavailable G-Protein-Biased Ligand at the μ-Opioid Receptor

Clin Pharmacol Drug Dev. 2020 Feb;9(2):256-266. doi: 10.1002/cpdd.721. Epub 2019 Jul 8.


TRV734 is an orally bioavailable G-protein-biased ligand at the μ-opioid receptor. In nonclinical studies it was potently analgesic while causing less gastrointestinal dysfunction than morphine, suggesting unique benefits in acute pain management. A 2-part, first-in-human study was conducted with ascending doses of TRV734 to explore its tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers. TRV734 was well tolerated over the dose range 2 to 250 mg when administered orally. Plasma TRV734 maximum concentration and area under the plasma concentration-time curve generally increased with dose, while time to maximum concentration was similar across doses (0.5-1.3 h). The half-life increased with dose from 10 mg through 150 mg (0.75-2.28 h) but was similar from 150 mg through 250 mg. Pupil constriction, confirming central nervous system μ-opioid receptor engagement, correlated with higher plasma TRV734 concentrations; the greatest reductions in pupil diameter occurring between 0 and 4 hours after dosing (-2.9 mm/h, with reduction peaking at 1 hour, and returning to baseline by 8 hours). Following administration of TRV734 125 mg under fasted or fed conditions, there was no significant difference in bioavailability when given as a solution or drug in capsule to fasted subjects. When drug in capsule was given to subjects following a high-fat meal, absorption was slowed, resulting in decreased peak concentrations, but area under the plasma concentration-time curve was not affected.

Keywords: TRV734; analgesic; biased ligand; opioid.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adult
  • Analgesics / adverse effects
  • Area Under Curve
  • Biological Availability
  • Cross-Over Studies
  • Fasting / blood
  • Fasting / metabolism*
  • GTP-Binding Proteins / administration & dosage*
  • GTP-Binding Proteins / pharmacokinetics
  • Half-Life
  • Healthy Volunteers
  • Humans
  • Ligands
  • Male
  • Middle Aged
  • Morphine / adverse effects
  • Opioid-Related Disorders / drug therapy
  • Pupil / drug effects*
  • Receptors, Opioid, mu / drug effects*
  • Receptors, Opioid, mu / metabolism
  • Safety
  • beta-Arrestins / metabolism


  • Analgesics
  • Ligands
  • Receptors, Opioid, mu
  • beta-Arrestins
  • Morphine
  • GTP-Binding Proteins