PMID- 28057550
OWN - NLM
STAT- MEDLINE
DCOM- 20170703
LR  - 20221207
IS  - 1879-0720 (Electronic)
IS  - 0928-0987 (Linking)
VI  - 100
DP  - 2017 Mar 30
TI  - Pharmacokinetics of LBPT and its primary metabolites, as well as tolerability in 
      the first-in-human study.
PG  - 87-93
LID - S0928-0987(16)30579-6 [pii]
LID - 10.1016/j.ejps.2016.12.038 [doi]
AB  - BACKGROUND: LBPT is a novel platelet-activating factor (PAF) receptor antagonist 
      that is developed for the treatment of rheumatoid arthritis. The purpose of this 
      first-in-human study was to evaluate the tolerability and safety of LBPT, to 
      investigate the pharmacokinetics of LBPT and its primary metabolites, as well as 
      to assess the food effect on the pharmacokinetics in healthy Chinese subjects. 
      MATERIALS AND METHODS: LBPT was evaluated in 2 clinical studies. The first study 
      was a double blind, placebo-controlled and ascending dose study. Eighty-five 
      healthy Chinese subjects received oral dose of 2, 4, 6, 8, 15, 25, 50, 75, 100, 
      125, 150, 225, 300, 400 or 500mg of LBPT or placebo. The pharmacokinetics of LBPT 
      and its primary metabolites were investigated in the last 4 dose cohorts. The 
      tolerability was evaluated by monitoring adverse events (AEs), physical 
      examinations, 12-lead electrocardiograms (ECG) and laboratory tests. The second 
      study was an open-label, 2-period cross-over study with a washout interval of 
      3days. Twelve subjects received 300mg of LBPT after an overnight fasting or a 
      high-fat breakfast. The pharmacokinetics of LBPT in subjects under fasted and fed 
      conditions were compared. RESULTS: LBPT was well tolerated up to 500mg-dose and 
      there were no serious AEs in the study. The incidence and severity of AEs were 
      closely related to dose. Following single oral administration of 225, 300, 400 
      and 500mg of LBPT, plasma C(max) was reached at 0.5h and the mean t(1/2) was 
      0.6-1.6h. Plasma exposure increased with dose escalation but proportionality was 
      not observed. LBPT was eliminated in forms of metabolites and 20-40% of the given 
      dose was recovered in urine. Compared with the subjects under fasting conditions, 
      AUC and C(max) were lower and t(max) was delayed in the fed subjects. CONCLUSION: 
      LBPT was well tolerated in healthy subjects with a pattern of dose-related AEs. 
      The pharmacokinetics was non-linear and was impacted by food intake.
CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
FAU - Wang, Hongyun
AU  - Wang H
AD  - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, 
      Beijing 100730, China.
FAU - Liu, Hongzhong
AU  - Liu H
AD  - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, 
      Beijing 100730, China.
FAU - Liu, Ming
AU  - Liu M
AD  - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, 
      Beijing 100730, China.
FAU - Wang, Wenjie
AU  - Wang W
AD  - Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, 
      China.
FAU - Zhu, Liya
AU  - Zhu L
AD  - Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, 
      China.
FAU - Huang, Haihong
AU  - Huang H
AD  - Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, 
      China.
FAU - Hu, Pei
AU  - Hu P
AD  - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, 
      Beijing 100730, China.
FAU - Jiang, Ji
AU  - Jiang J
AD  - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, 
      Beijing 100730, China. Electronic address: jiangjipumch@sohu.com.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20170103
PL  - Netherlands
TA  - Eur J Pharm Sci
JT  - European journal of pharmaceutical sciences : official journal of the European 
      Federation for Pharmaceutical Sciences
JID - 9317982
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Piperidines)
RN  - 0 (Platelet Membrane Glycoproteins)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (ethyl 1-(5-(4-chlorophenyl)-3-oxopent-4-enyl)piperidine-4-carboxylate)
RN  - 0 (platelet activating factor receptor)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Antirheumatic Agents/adverse effects/blood/*pharmacokinetics/urine
MH  - Area Under Curve
MH  - Asian People
MH  - Cross-Over Studies
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Female
MH  - *Food-Drug Interactions
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Piperidines/adverse effects/blood/*pharmacokinetics/urine
MH  - Platelet Membrane Glycoproteins/antagonists & inhibitors
MH  - Receptors, G-Protein-Coupled/antagonists & inhibitors
MH  - Young Adult
OTO - NOTNLM
OT  - LBPT
OT  - Pharmacokinetics
OT  - Platelet-activating factor
OT  - Rheumatoid arthritis
OT  - Tolerability
EDAT- 2017/01/07 06:00
MHDA- 2017/07/04 06:00
CRDT- 2017/01/07 06:00
PHST- 2016/09/14 00:00 [received]
PHST- 2016/12/01 00:00 [revised]
PHST- 2016/12/31 00:00 [accepted]
PHST- 2017/01/07 06:00 [pubmed]
PHST- 2017/07/04 06:00 [medline]
PHST- 2017/01/07 06:00 [entrez]
AID - S0928-0987(16)30579-6 [pii]
AID - 10.1016/j.ejps.2016.12.038 [doi]
PST - ppublish
SO  - Eur J Pharm Sci. 2017 Mar 30;100:87-93. doi: 10.1016/j.ejps.2016.12.038. Epub 
      2017 Jan 3.