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

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 microM 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 microM 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.

• Authors: Lindsay B Kilburn, Peter L Bonate, Susan M Blaney, Leticia McGuffey, Jed G Nuchtern, Robert Dauser, Patrick Thompson, Brian W Gibson, Stacey L Berg
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 64 Issue 2 Pg. 335-40 (Jul 2009) ISSN: 1432-0843 [Electronic] Germany
• PMID: 19043710 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carboxylic Acids
• Oligopeptides
• tasidotin

Topics

• Animals
• Carboxylic Acids (blood, cerebrospinal fluid, pharmacokinetics)
• Disease Models, Animal
• Injections, Intravenous
• Macaca mulatta
• Male
• Metabolic Clearance Rate
• Oligopeptides (blood, cerebrospinal fluid, pharmacokinetics)