title: Safety, pharmacokinetics, pharmacodynamics, and bioavailability of GSK2018682, a sphingosine-1-phosphate receptor modulator, in healthy volunteers.
abstract: The tolerability, pharmacokinetics, and pharmacodynamics of single (SD) and repeat (RD) doses of GSK2018682, a selective S1P1 receptor modulator, were evaluated in healthy volunteers. The bioavailability (BA) of different formulations and effects of food were also evaluated. SD of up to 24 mg and RD of up to 6 mg/day for 28 days were reasonably tolerated, despite higher incidences of gastrointestinal and cardiovascular adverse events compared to placebo. There was a linear relationship between dose and systemic exposure with a dose-independent half-life (t1/2 ) between 44.9 and 63.3 hours. GSK2018682 induced acute, transient and non-symptomatic decreases in heart rate and blood pressure. Dose-dependent reduction in absolute lymphocyte count (ALC), and all tested subsets, was observed to various degrees, up to a nadir of over 70% reduction from baseline. There was no difference in major pharmacokinetic parameters among three formulations of GSK2018682 and between fasted and fed subjects. However, there was a reduction in the extent of bradycardia following dosing in the fed state. Additionally, exercise induced robust increase in heart rate in subjects who had bradycardia following RD of GSK2018682 up to 6 mg, suggesting possible physiological methods of reducing the extent of S1P mediated bradycardia and subsequent AV-block.
authors.affiliation: GlaxoSmithKline Research and Development Center, Shanghai, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.affiliation: GlaxoSmithKline Research and Development Center, Shanghai, China.
authors.forename: Frank
authors.initials: F
authors.lastname: Gray
authors.affiliation: GlaxoSmithKline Research and Development Center, Shanghai, China.
authors.forename: Alex
authors.initials: A
authors.lastname: Henderson
authors.affiliation: GlaxoSmithKline Research and Development Center, Shanghai, China.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Hicks
authors.affiliation: GlaxoSmithKline Research and Development Center, Shanghai, China.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Yang
authors.affiliation: GlaxoSmithKline Research and Development Center, Shanghai, China.
authors.forename: Paul
authors.initials: P
authors.lastname: Thompson
authors.affiliation: GlaxoSmithKline Research and Development Center, Shanghai, China.
authors.forename: Johann
authors.initials: J
authors.lastname: Oliver
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D054537:Atrioventricular Block / Q000139:chemically induced / Q000503:physiopathology; D001315:Australia; D001682:Biological Availability; D001919:Bradycardia / Q000139:chemically induced / Q000503:physiopathology; D018592:Cross-Over Studies; D004339:Drug Compounding; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D010069:Oxadiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D049349:Receptors, Lysosphingolipid / Q000187:drug effects* / Q000378:metabolism; D016037:Single-Blind Method; D000081025:Sphingosine-1-Phosphate Receptors; D055815:Young Adult
chemical_list: C000625977:GSK2018682; D007211:Indoles; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors
keywords: GSK2018682; pharmacodynamics; pharmacokinetics; safety; sphingosine-1-phosphate receptor agonists