{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T23:32:28Z","timestamp":1780443148602,"version":"3.54.1"},"reference-count":20,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2014,2,10]],"date-time":"2014-02-10T00:00:00Z","timestamp":1391990400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2014,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>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\u2009mg and RD of up to 6\u2009mg\/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\u2010independent half\u2010life (t<jats:sub>1\/2<\/jats:sub>) between 44.9 and 63.3\u2009hours. GSK2018682 induced acute, transient and non\u2010symptomatic decreases in heart rate and blood pressure. Dose\u2010dependent 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\u2009mg, suggesting possible physiological methods of reducing the extent of S1P mediated bradycardia and subsequent AV\u2010block.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cpdd.98","type":"journal-article","created":{"date-parts":[[2013,12,17]],"date-time":"2013-12-17T06:32:39Z","timestamp":1387261959000},"page":"170-178","source":"Crossref","is-referenced-by-count":31,"title":["Safety, pharmacokinetics, pharmacodynamics, and bioavailability of GSK2018682, a sphingosine\u20101\u2010phosphate receptor modulator, in healthy volunteers"],"prefix":"10.1002","volume":"3","author":[{"given":"Jianfeng","family":"Xu","sequence":"first","affiliation":[{"name":"GlaxoSmithKline Research and Development Center Shanghai 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