Plasma and cerebrospinal fluid pharmacokinetics of ABT-888 after oral administration in non-human primates.
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.
Muscal
Jodi A
JA
Texas Children's Cancer Center, Baylor College of Medicine, and Texas Children's Hospital, 6621 Fannin Street, MC3-3320, Houston, TX 77030, USA.
Thompson
Patrick A
PA
Giranda
Vincent L
VL
Dayton
Brian D
BD
Bauch
Joy
J
Horton
Terzah
T
McGuffey
Leticia
L
Nuchtern
Jed G
JG
Dauser
Robert C
RC
Gibson
Brian W
BW
Blaney
Susan M
SM
Su
Jack M
JM
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
D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D011065:Poly(ADP-ribose) Polymerases