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Clin Pharmacol Drug Dev. 2019 Jul 8. doi: 10.1002/cpdd.721. [Epub ahead of print]

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

Author information

1
Trevena, Inc, Chesterbrook, PA, USA.
2
Flourtown, PA, USA.
3
Novartis, East Hanover, NJ, USA.
4
Intact Vascular, Wayne, PA, USA.
5
ICON Early Phase Services, San Antonio, TX, USA.

Abstract

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

PMID:
31286645
DOI:
10.1002/cpdd.721

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