title: Pharmacokinetics of LBPT and its primary metabolites, as well as tolerability in the first-in-human study.
abstract: 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.
  
  
  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 Cmaxwas reached at 0.5h and the mean t1/2was 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 Cmaxwere lower and tmaxwas delayed in the fed subjects.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Hongyun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Hongzhong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Wang
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Liya
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Haihong
authors.initials: H
authors.lastname: Huang
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100730, China. Electronic address: jiangjipumch@sohu.com.
authors.forename: Ji
authors.initials: J
authors.lastname: Jiang
mesh_terms: D000284:Administration, Oral; D000328:Adult; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D044466:Asian People; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D018565:Food-Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D010880:Piperidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; D010880:Piperidines; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C000596020:ethyl 1-(5-(4-chlorophenyl)-3-oxopent-4-enyl)piperidine-4-carboxylate; C039351:platelet activating factor receptor
keywords: LBPT; Pharmacokinetics; Platelet-activating factor; Rheumatoid arthritis; Tolerability