PMID- 28398597
OWN - NLM
STAT- MEDLINE
DCOM- 20180131
LR  - 20181221
IS  - 1552-4604 (Electronic)
IS  - 0091-2700 (Print)
IS  - 0091-2700 (Linking)
VI  - 57
IP  - 8
DP  - 2017 Aug
TI  - Results From the First-in-Human Study With Ozanimod, a Novel, Selective 
      Sphingosine-1-Phosphate Receptor Modulator.
PG  - 988-996
LID - 10.1002/jcph.887 [doi]
AB  - The sphingosine-1-phosphate 1 receptor (S1P(1R) ) is expressed by lymphocytes, 
      dendritic cells, and vascular endothelial cells and plays a role in the 
      regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid 
      organs. Ozanimod is an oral selective modulator of S1P(1R) and S1P(5R) receptors 
      in clinical development for the treatment of chronic immune-mediated, 
      inflammatory diseases. This first-in-human study characterized the safety, 
      pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy 
      volunteers using a range of single and multiple doses (7 and 28 days) and a 
      dose-escalation regimen. Ozanimod was generally well tolerated up to a maximum 
      single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events 
      (AEs) and no dose-limiting toxicities. The most common ozanimod-related AEs 
      included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited 
      linear PK, high steady-state volume of distribution (73-101 L/kg), moderate oral 
      clearance (204-227 L/h), and an elimination half-life of approximately 17 to 21 
      hours. Ozanimod produced a robust dose-dependent reduction in total peripheral 
      lymphocytes, with a median decrease of 65% to 68% observed after 28 days of 
      dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte 
      subtypes, causing marked decreases in cells expressing CCR7 and variable 
      decreases in subsets lacking CCR7. A dose-dependent negative chronotropic effect 
      was observed following the first dose, with the dose-escalation regimen 
      attenuating the first-dose negative chronotropic effect. Ozanimod safety, PK, and 
      PD properties support the once-daily regimens under clinical investigation.
CI  - (c) 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley 
      Periodicals, Inc. on behalf of American College of Clinical Pharmacology.
FAU - Tran, Jonathan Q
AU  - Tran JQ
AD  - Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
FAU - Hartung, Jeffrey P
AU  - Hartung JP
AD  - Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
FAU - Peach, Robert J
AU  - Peach RJ
AD  - Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
FAU - Boehm, Marcus F
AU  - Boehm MF
AD  - Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
FAU - Rosen, Hugh
AU  - Rosen H
AD  - Scripps Research Institute, San Diego, CA, USA.
FAU - Smith, Heather
AU  - Smith H
AD  - Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
FAU - Brooks, Jennifer L
AU  - Brooks JL
AD  - Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
FAU - Timony, Gregg A
AU  - Timony GA
AD  - Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
FAU - Olson, Allan D
AU  - Olson AD
AD  - Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
FAU - Gujrathi, Sheila
AU  - Gujrathi S
AD  - Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
FAU - Frohna, Paul A
AU  - Frohna PA
AD  - Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20170411
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - 0 (Indans)
RN  - 0 (Oxadiazoles)
RN  - 0 (Receptors, Lysosphingolipid)
RN  - Z80293URPV (ozanimod)
SB  - IM
MH  - Adult
MH  - Double-Blind Method
MH  - Fasting/metabolism
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - *Indans/adverse effects/blood/pharmacokinetics/pharmacology
MH  - Lymphocyte Count
MH  - Lymphocytes/drug effects
MH  - Male
MH  - Middle Aged
MH  - *Oxadiazoles/adverse effects/blood/pharmacokinetics/pharmacology
MH  - Receptors, Lysosphingolipid/metabolism
MH  - Young Adult
PMC - PMC5516232
OTO - NOTNLM
OT  - first-in-human study
OT  - ozanimod
OT  - pharmacodynamics
OT  - pharmacokinetics
OT  - safety
OT  - sphingosine-1-phosphate receptor
EDAT- 2017/04/12 06:00
MHDA- 2018/02/01 06:00
PMCR- 2017/07/19
CRDT- 2017/04/12 06:00
PHST- 2016/12/28 00:00 [received]
PHST- 2017/02/10 00:00 [accepted]
PHST- 2017/04/12 06:00 [pubmed]
PHST- 2018/02/01 06:00 [medline]
PHST- 2017/04/12 06:00 [entrez]
PHST- 2017/07/19 00:00 [pmc-release]
AID - JCPH887 [pii]
AID - 10.1002/jcph.887 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2017 Aug;57(8):988-996. doi: 10.1002/jcph.887. Epub 2017 Apr 
      11.