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Plasma and cerebrospinal fluid pharmacokinetics of tasidotin (ILX-651) and its metabolites in non-human primates

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Abstract

Purpose

To evaluate the plasma and cerebrospinal fluid (CSF) pharmacokinetics and CSF penetration of tasidotin and metabolites in a nonhuman primate model.

Methods

Tasidotin 0.75 mg/kg was administered intravenously. The plasma and CSF concentrations of tasidotin and its metabolites were determined. Pharmacokinetic parameters were estimated using model-independent and model-dependent methods.

Results

The mean (±SD) CSF:plasma AUC ratio for tasidotin was 1.1 ± 0.4. For tasidotin, tasidotin-C-carboxylate and desprolyl-tasidotin-C-carboxylate the plasma AUCs (mean ± SD) were 30 ± 10, 54 ± 19 and 12 ± 2 μM min, and apparent plasma half-lives were 27 ± 4, 229 ± 73 and 100 ± 29 min. The plasma clearance of tasidotin was 44 ± 14 ml/min/kg. The CSF AUC and half-life of tasidotin was 28 ± 10 μM min and 96 ± 40 min. The model-dependent plasma clearance was 35 ml/min/kg for tasidotin and 2 ml/min/kg for tasidotin-C-carboxylate.

Conclusions

Tasidotin penetrates into the CSF well and further evaluation of its activity in the treatment of central nervous system malignancies should be considered.

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Acknowledgments

This study was funded by Genzyme Oncology.

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Authors and Affiliations

  1. Texas Children’s Cancer Center, Baylor College of Medicine, 6621 Fannin St., MC:3-3320, Houston, TX, 77030, USA

    Lindsay B. Kilburn, Susan M. Blaney, Leticia McGuffey, Patrick Thompson & Stacey L. Berg

  2. Genzyme Oncology, 4545 Horizon Hill Blvd., San Antonio, TX, 78229, USA

    Peter L. Bonate

  3. Department of Surgery, Baylor College of Medicine, 6621 Fannin St., MC:650, Houston, TX, 77030, USA

    Jed G. Nuchtern

  4. Department of Neurosurgery, Baylor College of Medicine, 6621 Fannin St., MC:1230.01, Houston, TX, 77030, USA

    Robert Dauser

  5. Center for Comparative Medicine, Baylor College of Medicine, One Baylor Plaza, MS:145, Houston, TX, 77030, USA

    Brian W. Gibson

Authors
  1. Lindsay B. Kilburn
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  2. Peter L. Bonate
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  3. Susan M. Blaney
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  4. Leticia McGuffey
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  5. Jed G. Nuchtern
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  6. Robert Dauser
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  7. Patrick Thompson
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  8. Brian W. Gibson
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  9. Stacey L. Berg
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Corresponding author

Correspondence to Lindsay B. Kilburn.

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Kilburn, L.B., Bonate, P.L., Blaney, S.M. et al. Plasma and cerebrospinal fluid pharmacokinetics of tasidotin (ILX-651) and its metabolites in non-human primates. Cancer Chemother Pharmacol 64, 335–340 (2009). https://doi.org/10.1007/s00280-008-0875-7

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  • DOI: https://doi.org/10.1007/s00280-008-0875-7

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