First-time-in-human study with GSK1018921, a selective GlyT1 inhibitor: relationship between exposure and dizziness

Area of Science:

• Pharmacology and Toxicology
• Clinical Pharmacology

Background:

• Glycine transporter 1 (GlyT-1) inhibitors are investigated for potential therapeutic applications.
• Understanding the pharmacokinetics (PK), safety, and tolerability of novel drug candidates is crucial in early-stage clinical development.

Purpose of the Study:

• To evaluate the pharmacokinetics (PK), safety, and tolerability of GSK1018921, a novel GlyT-1 inhibitor.
• To assess the dose-response relationship of GSK1018921 in healthy human subjects.

Main Methods:

• A first-time-in-human (FTIH) study involving 25 healthy subjects.
• A five-period, two-cohort, crossover design administering single oral doses of GSK1018921 (0.5-280 mg) and placebo.
• Pharmacokinetic profiling and safety assessments, including adverse event monitoring.
• A Markov-chain logistic regression model in NONMEM to predict dizziness probability.

Main Results:

• GSK1018921 exhibited dose-proportional pharmacokinetics (PK) with a terminal half-life of approximately 17 hours.
• Dizziness was the most frequent adverse event, occurring in 22-88% of subjects at doses of 70-280 mg.
• The onset and resolution of dizziness correlated with drug plasma concentrations, with full resolution within 10-12 hours.

Conclusions:

• GSK1018921 demonstrates predictable dose-proportional PK and is generally tolerated in healthy subjects at single oral doses up to 280 mg.
• Dizziness is a dose-dependent, transient adverse effect that can be modeled based on plasma concentration.
• Exposure associated with 80% GlyT-1 receptor occupancy is predicted to be well tolerated.