First clinical experience with TRV130: pharmacokinetics and pharmacodynamics in healthy volunteers

J Clin Pharmacol. 2014 Mar;54(3):351-7. doi: 10.1002/jcph.207. Epub 2014 Jan 28.


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 over 1 hour. TRV130 geometric mean exposure and Cmax were dose-linear, with AUC0-inf of 2.52 to 205.97 ng h/mL and Cmax of 1.04 to 102.36 ng/mL across the dose range tested, with half-life of 1.6-2.7 hours. A 1.5 mg dose of TRV130 was also well-tolerated when administered as 30, 15, 5, and 1 minute infusions. TRV130 pharmacokinetics were modestly affected by CYP2D6 phenotype: clearance was reduced by 53% in CYP2D6 poor metabolizers.TRV130 caused dose- and exposure-related pupil constriction, confirming central compartment µ-opioid receptor engagement. Marked pupil constriction was noted at 2.2, 4, and 7 mg doses. Nausea and vomiting observed at the 7 mg dose limited further dose escalation. These findings suggest that TRV130 may have a broad margin between doses causing µ-opioid receptor-mediated pharmacology and doses causing µ-opioid receptor-mediated intolerance.

Trial registration: NCT01514578.

Keywords: TRV130; analgesic; biased ligand; opioid.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Administration, Intravenous
  • Adult
  • Analgesics* / administration & dosage
  • Analgesics* / adverse effects
  • Analgesics* / pharmacokinetics
  • Analgesics* / pharmacology
  • Cross-Over Studies
  • Double-Blind Method
  • Healthy Volunteers
  • Humans
  • Ligands
  • Male
  • Middle Aged
  • Nausea / chemically induced
  • Receptors, Opioid, mu / metabolism
  • Spiro Compounds* / administration & dosage
  • Spiro Compounds* / adverse effects
  • Spiro Compounds* / pharmacokinetics
  • Spiro Compounds* / pharmacology
  • Thiophenes* / administration & dosage
  • Thiophenes* / adverse effects
  • Thiophenes* / pharmacokinetics
  • Thiophenes* / pharmacology
  • Vomiting / chemically induced
  • Young Adult


  • ((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine
  • Analgesics
  • Ligands
  • Receptors, Opioid, mu
  • Spiro Compounds
  • Thiophenes

Associated data