Plasma and cerebrospinal fluid pharmacokinetics of intravenously administered ABT-751 in non-human primates.
OBJECTIVE
ABT-751 is an orally bioavailable sulfonamide that binds to the colchicine binding site on beta-tubulin and inhibits microtubule polymerization. The plasma and cerebrospinal fluid (CSF) pharmacokinetics of ABT-751, after a short intravenous infusion, were evaluated in a non-human primate (Macaca mulatta) model that is highly predictive of the CSF penetration of drugs in humans.


METHODS
Plasma and CSF samples were collected over 24 h after 7.5 mg/kg (150 mg/m2) ABT-751 infused over 0.25-0.70 h, and ABT-751 concentrations in plasma and CSF were quantified using a validated HPLC-MS/MS assay. Pharmacokinetic parameters in plasma and CSF were derived using non-compartmental methods.


CONCLUSIONS
Plasma disappearance was bi-exponential with a terminal half-life of 13 h. The mean +/- SD clearance was 100 +/- 18 ml/min m2, the mean +/- SD volume of distribution at steady state was 1.3 +/- 0.5 l/kg, and the mean +/- SD mean residence time was 4.6 +/- 1.8 h. The mean +/- SD peak ABT-751 concentration in CSF was 0.26 +/- 0.08 microM, and the mean +/- SD CSF half-life of 1.3 +/- 0.3 h. CSF penetration was limited (mean +/- SD AUC(CSF):AUC(plasma), 1.1 +/- 0.3%) relative to total (protein-bound + free) plasma drug concentrations, but the CSF concentrations approximated the estimated free drug concentrations in plasma.
Cho
Steve Y
SY
Pediatric Oncology Branch, National Cancer Institute (NCI), Bethesda, MD 20892, USA.
Fox
Elizabeth
E
McCully
Cynthia
C
Bauch
Joy
J
Marsh
Kennan
K
Balis
Frank M
FM
D000818:Animals; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D013449:Sulfonamides / Q000097:blood* / Q000134:cerebrospinal fluid*
C490492:ABT751; D013449:Sulfonamides