Plasma and cerebrospinal fluid pharmacokinetics of SU5416 after intravenous administration in nonhuman primates.
OBJECTIVE
SU5416 is a small, lipophilic synthetic molecule that selectively inhibits the tyrosine kinase activity of the VEGF receptor Flk-1/KDR. The role of this agent in brain tumors is currently being investigated. Pharmacokinetic studies of SU5416 have been performed in humans; however, there have been no studies of its penetration in the cerebrospinal fluid (CSF). We studied the pharmacokinetics of SU5416 in plasma and CSF after intravenous (i.v.) administration using a nonhuman primate model that is highly predictive of the CSF penetration in humans.


METHODS
SU5416 (85 mg/m(2), about 3.8 mg/kg) was administered i.v. over 20 min to four nonhuman primates. Serial plasma and CSF samples were obtained prior to, during, and after completion of the infusion for determination of SU5416 concentrations. SU5416 was measured in plasma and CSF using high-performance liquid chromatography (HPLC). Concentration-versus-time data were modeled using model-independent and model-dependent methods.


RESULTS
Peak plasma concentrations ranged from 6.3 to 14.5 microM and the mean plasma AUC was 620+/-180 microM.min. Disappearance of SU5416 from the plasma was best described by a one-compartment model with a half-life of 39+/-2.9 min. The volume of distribution was 36+/-11 l/m(2) and the clearance was 0.62+/-0.2 l/min per m(2). SU4516 was not quantifiable in the CSF.


CONCLUSIONS
There is minimal penetration of SU5416 into the CSF after i.v. administration. The very low CNS exposure to SU5416 after i.v. dosing suggests that this agent is not optimal for the treatment of leptomeningeal tumors.
Renbarger
Jamie
J
Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin Street, Houston, TX 77030, USA.
Aleksic
Alexander
A
McGuffey
Leticia
L
Dauser
Robert
R
Berg
Stacey
S
Blaney
Susan
S
D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000134:cerebrospinal fluid*; D006207:Half-Life; D007211:Indoles / Q000008:administration & dosage / Q000097:blood* / Q000134:cerebrospinal fluid*; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood* / Q000134:cerebrospinal fluid*
D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D011505:Protein-Tyrosine Kinases