title: Plasma and cerebrospinal fluid pharmacokinetics of tasidotin (ILX-651) and its metabolites in non-human primates.
abstract: OBJECTIVE
  To evaluate the plasma and cerebrospinal fluid (CSF) pharmacokinetics and CSF penetration of tasidotin and metabolites in a nonhuman primate model.
  
  
  METHODS
  Tasidotin 0.75 mg/kg was administered intravenously. The plasma and CSF concentrations of tasidotin and its metabolites were determined. Pharmacokinetic parameters were estimated using model-independent and model-dependent methods.
  
  
  RESULTS
  The mean (+/-SD) CSF:plasma AUC ratio for tasidotin was 1.1 +/- 0.4. For tasidotin, tasidotin-C-carboxylate and desprolyl-tasidotin-C-carboxylate the plasma AUCs (mean +/- SD) were 30 +/- 10, 54 +/- 19 and 12 +/- 2 microM min, and apparent plasma half-lives were 27 +/- 4, 229 +/- 73 and 100 +/- 29 min. The plasma clearance of tasidotin was 44 +/- 14 ml/min/kg. The CSF AUC and half-life of tasidotin was 28 +/- 10 microM min and 96 +/- 40 min. The model-dependent plasma clearance was 35 ml/min/kg for tasidotin and 2 ml/min/kg for tasidotin-C-carboxylate.
  
  
  CONCLUSIONS
  Tasidotin penetrates into the CSF well and further evaluation of its activity in the treatment of central nervous system malignancies should be considered.
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin St., MC:3-3320, Houston, TX 77030, USA. lbkilbur@txccc.org
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Kilburn
authors.forename: Peter L
authors.initials: PL
authors.lastname: Bonate
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Leticia
authors.initials: L
authors.lastname: McGuffey
authors.forename: Jed G
authors.initials: JG
authors.lastname: Nuchtern
authors.forename: Robert
authors.initials: R
authors.lastname: Dauser
authors.forename: Patrick
authors.initials: P
authors.lastname: Thompson
authors.forename: Brian W
authors.initials: BW
authors.lastname: Gibson
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Berg
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D009842:Oligopeptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
chemical_list: D002264:Carboxylic Acids; D009842:Oligopeptides; C504233:tasidotin