Plasma and cerebrospinal fluid pharmacokinetics of ABT-888 after oral administration in non-human primates

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. 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. The CSF penetration of ABT-888 was 57 +/- A 7% (mean +/- A SD). The peak ABT-888 concentration in the plasma was 0.62 +/- A 0.18 mu M. Plasma and CSF AUC(0-a) were 3.7 +/- A 1.7 and 2.1 +/- A 0.8 mu M h. PARP inhibition in peripheral blood mononuclear cells was evident 2 h after ABT-888 administration. 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.