title: Formulation design and evaluation of liposomal sepantronium bromide (YM155), a small-molecule survivin suppressant, based on pharmacokinetic modeling and simulation.
abstract: OBJECTIVE
  Sepantronium bromide (YM155) is administered by 168-hour continuous infusions in clinical studies due to its time-dependent pharmacological efficacy and rapid elimination from plasma. To enable more convenient administration, i.e., bolus injections with low frequency, we prepared liposomal formulations of YM155 and evaluated their antitumor activities.
  
  
  METHODS
  A kinetic simulation model of liposomal YM155 to predict the free drug concentration in both tumor and plasma was developed. A liposomal formulation with the target drug release rate was prepared based on the simulation. Antitumor activities of the formulation were examined in various tumor xenograft mouse models. In addition, antitumor activities of liposomal formulations with different drug release rates were compared in order to confirm the validity of the simulation-based prediction.
  
  
  RESULTS
  Liposomal YM155 with the release half-life of 48 h was prepared as a promising formulation. This formulation showed significantly potent antitumor activities in tumor xenograft models by weekly bolus injections. Further studies demonstrated that this release rate was optimal for YM155 in terms of both efficacy and safety.
  
  
  CONCLUSIONS
  We successfully developed a liposomal formulation of YM155 that could substitute for long-term continuous infusion of the drug solution in clinical settings by being given as weekly bolus injections.
authors.affiliation: Pharmaceutical Research and Technology Labs., Technology, Astellas Pharma Inc.,, 180 Ozumi, Yaizu-shi,, Shizuoka, 425-0072, Japan, kohsuke.shakushiro@astellas.com.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Shakushiro
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kawano
authors.forename: Mari
authors.initials: M
authors.lastname: Nakata
authors.forename: Aya
authors.initials: A
authors.lastname: Kita
authors.forename: Atsushi
authors.initials: A
authors.lastname: Maeda
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Watanabe
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sako
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D004337:Drug Carriers / Q000737:chemistry*; D015195:Drug Design; D065546:Drug Liberation; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D008081:Liposomes; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009285:Naphthoquinones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077022:Survivin; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes; D009285:Naphthoquinones; D000077022:Survivin; C523798:sepantronium