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

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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 AUC0–∞ 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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Acknowledgments

We thank Gaye Jenkins for technical assistance. National Cancer Institute K12 Pediatric Clinical Oncology Research Training Program 5K12CA90433-07 (JA Muscal), Mentored Specialized Clinical Investigator Development Award in Pediatric Pharmacology (PA Thompson), The Childhood Brain Tumor Foundation (JM Su), National Cancer Institute K23 Career Development Award 1K23CA113721 (JM Su).

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Authors and Affiliations

  1. Texas Children’s Cancer Center, Baylor College of Medicine, 6621 Fannin Street, MC3-3320, Houston, TX, 77030, USA

    Jodi A. Muscal, Patrick A. Thompson, Terzah Horton, Leticia McGuffey, Susan M. Blaney & Jack M. Su

  2. Abbott Laboratories, Abbott Park, IL, USA

    Vincent L. Giranda, Brian D. Dayton & Joy Bauch

  3. Texas Childrens’s Hospital, Baylor College of Medicine, Houston, TX, USA

    Jed G. Nuchtern & Robert C. Dauser

  4. Center for Comparative Medicine, Baylor College of Medicine, Houston, TX, 77030, USA

    Brian W. Gibson

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  1. Jodi A. Muscal
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Correspondence to Jack M. Su.

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Muscal, J.A., Thompson, P.A., Giranda, V.L. et al. Plasma and cerebrospinal fluid pharmacokinetics of ABT-888 after oral administration in non-human primates. Cancer Chemother Pharmacol 65, 419–425 (2010). https://doi.org/10.1007/s00280-009-1044-3

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  • DOI: https://doi.org/10.1007/s00280-009-1044-3

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