title: Plasma and cerebrospinal fluid pharmacokinetics of ABT-888 after oral administration in non-human primates.
abstract: OBJECTIVE
  ABT-888 inhibits poly(ADP-ribose) polymerase (PARP) and may enhance the efficacy of chemotherapy and radiation in CNS tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of ABT-888 in a non-human primate (NHP) model that is highly predictive of human CSF penetration.
  
  
  METHODS
  ABT-888, 5 mg/kg, was administered orally to three NHPs. Serial blood and CSF samples were obtained. Plasma and CSF concentrations of ABT-888 were measured using LC/MS/MS, and the resulting concentration versus time data were evaluated using non-compartmental and compartmental PK methods.
  
  
  RESULTS
  The CSF penetration of ABT-888 was 57+/-7% (mean+/-SD). The peak ABT-888 concentration in the plasma was 0.62+/-0.18 microM. Plasma and CSF AUC0-infinity were 3.7+/-1.7 and 2.1+/-0.8 microM h. PARP inhibition in peripheral blood mononuclear cells was evident 2 h after ABT-888 administration.
  
  
  CONCLUSIONS
  The CSF penetration of ABT-888 after oral administration was 57%. Plasma and CSF concentrations were in the range that has been shown to inhibit PARP activity in vivo in humans.
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, and Texas Children's Hospital, 6621 Fannin Street, MC3-3320, Houston, TX 77030, USA.
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Muscal
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Thompson
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Giranda
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dayton
authors.forename: Joy
authors.initials: J
authors.lastname: Bauch
authors.forename: Terzah
authors.initials: T
authors.lastname: Horton
authors.forename: Leticia
authors.initials: L
authors.lastname: McGuffey
authors.forename: Jed G
authors.initials: JG
authors.lastname: Nuchtern
authors.forename: Robert C
authors.initials: RC
authors.lastname: Dauser
authors.forename: Brian W
authors.initials: BW
authors.lastname: Gibson
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Jack M
authors.initials: JM
authors.lastname: Su
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001562:Benzimidazoles / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013997:Time Factors
chemical_list: D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D011065:Poly(ADP-ribose) Polymerases