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01-02-2010 | Original Article

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

Authors: Jodi A. Muscal, Patrick A. Thompson, Vincent L. Giranda, Brian D. Dayton, Joy Bauch, Terzah Horton, Leticia McGuffey, Jed G. Nuchtern, Robert C. Dauser, Brian W. Gibson, Susan M. Blaney, Jack M. Su

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2010

Abstract

Purpose

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 μM. Plasma and CSF AUC_0–∞ were 3.7 ± 1.7 and 2.1 ± 0.8 μM h. PARP inhibition in peripheral blood mononuclear cells was evident 2 h after ABT-888 administration.

Conclusion

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.

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Title: Plasma and cerebrospinal fluid pharmacokinetics of ABT-888 after oral administration in non-human primates
Authors: Jodi A. Muscal
Patrick A. Thompson
Vincent L. Giranda
Brian D. Dayton
Joy Bauch
Terzah Horton
Leticia McGuffey
Jed G. Nuchtern
Robert C. Dauser
Brian W. Gibson
Susan M. Blaney
Jack M. Su
Publication date: 01-02-2010
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2010
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-009-1044-3

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Purpose

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