title: First clinical experience with TRV130: pharmacokinetics and pharmacodynamics in healthy volunteers.
abstract: 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.
authors.affiliation: Trevena, Inc., King of Prussia, PA, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Soergel
authors.forename: Ruth Ann
authors.initials: RA
authors.lastname: Subach
authors.forename: Brian
authors.initials: B
authors.lastname: Sadler
authors.forename: John
authors.initials: J
authors.lastname: Connell
authors.forename: Alan S
authors.initials: AS
authors.lastname: Marion
authors.forename: Conrad L
authors.initials: CL
authors.lastname: Cowan
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Violin
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lark
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013141:Spiro Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult
chemical_list: C586842:((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine; D000700:Analgesics; D008024:Ligands; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds; D013876:Thiophenes
keywords: TRV130; analgesic; biased ligand; opioid