title: First-time-in-human study with GSK1018921, a selective GlyT1 inhibitor: relationship between exposure and dizziness.
abstract: The pharmacokinetics (PK), safety, and tolerability of GSK1018921, a glycine transporter 1 (GlyT-1) inhibitor, were assessed in this first-time-in-human (FTIH) study. Single oral doses ranging from 0.5 to 280 mg and placebo were administered to 25 healthy subjects in a five-period, two-cohort, crossover study. GSK1018921 showed dose-proportional PK with a terminal half-life of ~17 h. The subjects reported dizziness with a dose-dependent frequency of 22-88% at doses of 70-280 mg. The time course of the dizziness paralleled the PK of the drug, with peak response at 2 h after the dose, consistent with time to maximum plasma concentration (T(max)). The dizziness was resolved by 10-12 h in all subjects. A Markov-chain logistic regression model was implemented in NONMEM to determine the probability of developing dizziness as a function of the plasma concentration of the compound. Frequency, onset (<1 h), and offset (4 h) were well described by the model. Exposure resulting in 80% receptor occupancy is predicted to be well tolerated.
authors.affiliation: Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, Durham, North Carolina, USA. daniele.x.ouellet@gsk.com
authors.forename: D
authors.initials: D
authors.lastname: Ouellet
authors.forename: S
authors.initials: S
authors.lastname: Sutherland
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.forename: P
authors.initials: P
authors.lastname: Griffini
authors.forename: V
authors.initials: V
authors.lastname: Murthy
mesh_terms: D000293:Adolescent; D000328:Adult; D001549:Benzamides / Q000009:adverse effects* / Q000378:metabolism*; D015331:Cohort Studies; D018592:Cross-Over Studies; D004244:Dizziness / Q000139:chemically induced* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000009:adverse effects* / Q000378:metabolism*; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D001549:Benzamides; C562323:GSK 1018921; D050487:Glycine Plasma Membrane Transport Proteins; D011759:Pyrrolidines; C493268:SLC6A9 protein, human