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

Area of Science:

• Pharmacology
• Pain Management
• Clinical Pharmacology

Background:

• TRV734 is an orally bioavailable G-protein-biased ligand targeting the μ-opioid receptor.
• Nonclinical studies indicated potent analgesia with reduced gastrointestinal dysfunction compared to morphine.
• This suggests potential advantages for TRV734 in managing acute pain.

Purpose of the Study:

• To evaluate the tolerability, pharmacokinetics, and pharmacodynamics of TRV734 in a first-in-human study.
• To explore the dose-ranging effects of oral TRV734 in healthy volunteers.
• To assess μ-opioid receptor engagement via pupil constriction.

Main Methods:

• A 2-part, ascending dose, first-in-human study in healthy volunteers.
• Oral administration of TRV734 across a dose range of 2 to 250 mg.
• Pharmacokinetic sampling, pupil diameter measurements, and assessment of tolerability.

Main Results:

• TRV734 was well tolerated across the studied oral dose range (2-250 mg).
• Pharmacokinetics showed dose-dependent increases in Cmax and AUC, with a moderate half-life increase up to 150 mg.
• Pupil constriction, indicative of central μ-opioid receptor engagement, correlated with TRV734 plasma concentrations.

Conclusions:

• TRV734 is well-tolerated and exhibits predictable pharmacokinetics and pharmacodynamics in healthy humans.
• The drug engages central μ-opioid receptors, as evidenced by pupil constriction.
• TRV734 shows promise as a potential therapeutic agent for acute pain management.