Plasma and cerebrospinal fluid pharmacokinetics of tasidotin (ILX-651) and its metabolites in non-human primates.
OBJECTIVE
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.
Kilburn
Lindsay B
LB
Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin St., MC:3-3320, Houston, TX 77030, USA. lbkilbur@txccc.org
Bonate
Peter L
PL
Blaney
Susan M
SM
McGuffey
Leticia
L
Nuchtern
Jed G
JG
Dauser
Robert
R
Thompson
Patrick
P
Gibson
Brian W
BW
Berg
Stacey L
SL
D000818:Animals; D002264:Carboxylic Acids / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D009842:Oligopeptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
D002264:Carboxylic Acids; D009842:Oligopeptides; C504233:tasidotin